Rapid delivery and/or receiving of fluids

ABSTRACT

The present invention generally relates to systems and methods for delivering and/or receiving a substance or substances such as blood, from subjects, e.g., from the skin and/or from beneath the skin. In one aspect, the present invention is generally directed to devices and methods for receiving or extracting blood from a subject, e.g., from the skin and/or from beneath the skin, using devices containing a fluid transporter (for example, one or more microneedles), and a storage chamber having an internal pressure less than atmospheric pressure prior to receiving blood. In some cases, the device may be self-contained, and in certain instances, the device can be applied to the skin, and activated to receive blood from the subject. The device, or a portion thereof, may then be processed to determine the blood and/or an analyte within the blood, alone or with an external apparatus. For example, blood may be received from the device, and/or the device may contain sensors or agents able to determine the blood and/or an analyte suspected of being contained in the blood. In another aspect, the present invention is generally directed to arrangements of skin insertion objects such as microneedles and methods of forming and arranging skin insertion objects. Other aspects of the present invention are directed at other devices for receiving blood (or other bodily fluids, e.g., interstitial fluid), kits involving such devices, methods of making such devices, methods of using such devices, and the like.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/367607, filed Jul. 26, 2010, entitled “RapidDelivery and/or Withdrawal of Fluids,” by Chickering, et al. Thisapplication is incorporated herein by reference.

FIELD OF INVENTION

The present invention generally relates to systems and methods fordelivering and/or receiving a substance or substances such as bloodand/or drugs, with respect to subjects, e.g., at and/or beneath theskin, and in some cases, with relatively little pain.

BACKGROUND

Phlebotomy or venipuncture is the process of obtaining intravenousaccess for the purpose of intravenous therapy or obtaining a sample ofvenous blood. This process is typically practiced by medicalpractitioners, including paramedics, phlebotomists, doctors, nurses, andthe like. Substantial equipment is needed to obtain blood from asubject, including the use of evacuated (vacuum) tubes, e.g., such asthe Vacutainer™ (Becton, Dickinson and company) and Vacuette™ (GreinerBio-One GmBH) systems. Other equipment includes hypodermic needles,syringes, and the like. However, such procedures are complicated andrequire sophisticated training of practitioners, and often cannot bedone in non-medical sellings. Accordingly, improvements in methods ofobtaining blood or other fluids from the skin are still needed.

SUMMARY OF THE INVENTION

The present invention generally relates to systems and methods fordelivering and/or receiving a substance or substances such as blood,from subjects, e.g., from the skin and/or from beneath the skin. Thesubject matter of the present invention involves, in some cases,interrelated products, alternative solutions to a particular problem,and/or a plurality of different uses of one or more systems and/orarticles.

In one aspect of the invention, microneedles in an array may be arrangedto maximize a density of microneedles per unit area of the array. Forexample, a number of microneedles in a circular array according to oneembodiment of the invention may be about two times the number ofmicroneedles in a rectangular array having the same footprint size.Improved density may be achieved in some embodiments by havingmicroneedles arranged (while the microneedles are lying in a commonplane and prior to bending a penetrating portion of the needles upwardfrom the plane) so that the microneedles generally “point” towards atleast one other microneedle in the array and such that the microneedlesore generally not parallel with each other. For example, in oneembodiment, a method for forming an array of microneedles may includesteps of providing a layer of material having opposed substantiallyplanar sides, and etching the layer of material to define a plurality ofmicroneedles. The microneedles may be formed from the layer such thatbases of the microneedles are arranged at a periphery of a closed loopand each of the microneedles extends toward a center of the closed loop.Since the microneedles in this illustrative embodiment may pointradially inwardly, the microneedles will generally not be parallel witheach other (although some needles may be parallel with one or more otherneedles). This configuration has been found to make efficient use ofmaterial in the layer and provide a higher total number of microneedlesfor a given area than other arrangements, such as a rectangular array inwhich the microneedles are all parallel to each other. After forming themicroneedles from the layer, the penetrating portions of themicroneedles may be bent away from the bases (i.e., out of the commonplane of the layer) so that the penetrating portions are arranged forinsertion into skin or other material. That is, the penetrating portionsmay be bent upwardly from the common plane of the layer so that thepenetrating portions are arranged at an angle relative to the plane ofthe closed loop.

In another illustrative embodiment, an array of microneedles may includea plurality of microneedles that each include a base portion and apenetrating portion. The base portions of the plurality of needles maybe arranged at the periphery of a closed loop lying in a common plane,and the penetrating portions may extend at an angle away from the planeof the closed loop. Such an arrangement may help improve a packingdensity of needles for the array, e.g., by allowing the needles to beformed from a sheet of material while making efficient use of thematerial, and/or provide for an array with Improved material transferproperties, e.g., by allowing the microneedles to provide a flow channelfor fluid exiting from skin penetrated by the needles.

In another aspect of the invention, the microneedle arrangement includesa first plurality of microneedles that each include a base portion and apenetrating portion, the base portions of the first plurality ofmicroneedles being arranged at the periphery of a first closed looplying in a plane, the penetrating portions of the first plurality ofmicroneedles each extending at a respective angle away from the plane ofthe first closed loop. The arrangement also includes a second pluralityof microneedles that each include a base portion and a penetratingportion, the base portions of the second plurality of microneedles beingarranged at a periphery of a second closed loop lying in the plane, thesecond closed loop being larger than, and surrounding, the first closedloop, the penetrating portions of the second plurality of microneedleseach extending at a respective angle away from the plane of the secondclosed loop. This arrangement may further increase the packing densityof needles. In some illustrative embodiments, the closed loops arecircles. In one illustrative embodiment, the closed loops are concentriccircles.

In another aspect of the invention, a method for forming a microneedlearrangement includes providing a layer of material having opposedsubstantially planar sides, etching the layer of material to define aplurality of microneedles such that bases of the microneedles arearranged at a periphery of a first closed loop and each of themicroneedles extends toward a center of the first closed loop, andetching the layer of material to define a second plurality ofmicroneedles with bases arranged at a periphery of a second closed loopthat is arranged around the first closed loop.

In one aspect, the present invention is generally directed tomicroneedles for insertion into the skin for the purpose of deliveringtherapeutics, such as medicines, drugs, etc., or receiving fluids, suchas blood or interstitial fluid. For example, microneedles may beinserted into skin and then withdrawn, allowing blood or other fluid toflow from the skin. In other arrangements, the microneedles may remainin the skin after insertion (at least temporarily), and be coated, haveone or more channels, be capable of degrading or dissolving, orotherwise be arranged to allow fluid to flow from the skin. In oneembodiment, microneedles may include a tip having a point that serves asa leading contact surface. Providing a leading contact surface on amicroneedle in the form of a point may help reduce a force needed toinsert the microneedle into skin or other material, may help themicroneedle maintain a straight or other desired trajectory when passingthrough skin, and/or other features. In one embodiment, the point may beformed at the intersection of four or more surfaces and may reduce aforce needed to insert the needle into skin or other material. Inanother embodiment, a microneedle may have a knife edge, e.g., at leasta portion of the edge of the microneedle may be formed by beveledsurfaces. The knife edge may have a V-shape and may be symmetrical orasymmetrical. The knife edge may be formed using an etching process,e.g., an isotropic chemical etching process used in combination with aphotolithographic patterning or other lithographic patterning process toform the microneedle from a layer of metal or other material.

In yet another aspect, the invention is directed to a kit. In one set ofembodiments, the kit includes a fluid sample device comprising a fluidtransporter for receiving fluid from the subject and a storage chamberfor receiving fluid withdrawn from the subject via the fluidtransporter, and an external analytical apparatus having a port formating with a port on the fluid sample device.

In another aspect, the present invention is directed to a method ofmaking one or more of the embodiments described herein, for example,devices for receiving blood from a subject. In another aspect, thepresent invention is directed to a method of using one or more of theembodiments described herein, for example, devices for receiving bloodfrom a subject.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control. If twoor more documents incorporated by reference include conflicting and/orinconsistent disclosure with respect to each other, then the documenthaving the later effective dale shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIGS. 1A-1B illustrate devices according to certain embodiments of theinvention;

FIGS. 2A-2C illustrate devices according to various embodiments of theinvention;

FIG. 2D illustrates a kit containing more than one device, in yetanother embodiment of the invention;

FIG. 2E illustrates a device according to still another embodiment ofthe invention;

FIG. 3 illustrates a device in one embodiment of the invention, having avacuum chamber;

FIG. 4 illustrates a device in another embodiment of the invention,having a vacuum chamber and a storage chamber;

FIG. 5 illustrates a device in yet another embodiment of the invention,having a flow controller;

FIG. 6 illustrates a device in yet another embodiment of the invention,having an exit port;

FIG. 7 illustrates a device according to another embodiment of theinvention;

FIG. 8 illustrates a device containing a fluid reservoir, in anotherembodiment of the invention;

FIG. 9 illustrates an adaptor according to one embodiment of theinvention;

FIGS. 10A-10C illustrate a device in still another embodimentillustrating a deployment actuator;

FIG. 11 illustrates yet another embodiment of the invention in which adevice is actuated by a deployment actuator;

FIGS. 12A and 12B illustrate yet another embodiment of the invention, inwhich a device is actuated by a deployment actuator, at different stagesof operation of the device;

FIG. 13 is a perspective view of a microneedle that is useable in somemicroneedle array arrangements in accordance with an aspect of theinvention;

FIG. 14 shows a perspective view of a microneedle having a knife edge inan illustrative embodiment;

FIG. 15 is a cross sectional view of the microneedle of FIG. 14 alongthe line 15-15;

FIG. 16 is a top view of the microneedle in FIG. 14;

FIG. 17 shows a perspective view of a microneedle having a knife edge inanother illustrative embodiment;

FIGS. 18 and 19 schematically show two steps in a method for formingmicroneedles in an illustrative embodiment;

FIG. 20 shows an illustrative array of microneedles in which eachmicroneedle has the configuration as shown in FIG. 14;

FIG. 21 shows an illustrative array of microneedles in which eachmicroneedle has the configuration as shown in FIG. 11;

FIG. 22 schematically shows steps in a method for forming the array ofFIG. 20;

FIG. 23 shows a plan view of the array of FIG. 21 prior to a bendingstep

FIG. 24 shows a plan view of a rectangular microneedle array prior to abending step;

FIG. 25 shows a perspective view of a microneedle having a beveled edgein an illustrative embodiment;

FIG. 26 is a cross sectional view of the microneedle of FIG. 25 alongthe line 26-26; and

FIG. 27 shows an illustrative array of microneedles having two groups ofmicroneedles arranged with respect to concentric closed loops.

DETAILED DESCRIPTION

The present invention generally relates to systems and methods forreceiving a substance from a subject, e.g. received from the skin and/orfrom beneath the skin of the subject, and/or for delivering a substanceto a subject, e.g. delivering a substance to the skin and/or to alocation beneath the skin of a subject. Throughout the application, thephrase “from the skin” is used to mean from the top or outer surface ofthe skin, from within the skin, and/or from beneath the skin. Likewise,“to the skin” is used to mean to the top or outer surface of the skin,to within the skin, and/or to beneath the skin. The device, in somecases, may be interfaced with external equipment to determine an analytecontained within a fluid contained within or collected by the device.For example, the device may be mounted on an external holder, the devicemay include a port for transporting fluid out of the device, the devicemay include a window for interrogating a fluid contained within thedevice, or the like.

The received fluid may be any suitable bodily fluid, such asinterstitial fluid, other skin-associated material, mucosal material orfluid, whole blood, perspiration, saliva, plasma, tears, lymph, urine,plasma, or any other bodily fluid, or combinations thereof. Substancesreceived from a subject can include solid or semi-solid material such asskin, cells, or any other substance from the subject. Substances thatcan be delivered to a subject in accordance with some embodiments of theinvention include diagnostic substances, therapeutic substances such asdrugs, and the like. Various embodiments of the invention are describedbelow in the context of delivering or receiving a fluid, such as blood,from or through the skin. It is to be understood that in all embodimentsherein, regardless of the specific exemplary language used (e.g.,receiving blood), the devices and methods of other embodiments of theinvention can be used for receiving any substance from the skin and/orfrom beneath the skin of the subject, and/or for delivering anysubstance to the subject, e.g. to the skin and/or a location beneath theskin of the subject.

In one aspect, the present invention is generally directed to devicesand methods for receiving or extracting blood or other bodily fluidsfrom a subject, e.g., from the skin and/or from beneath the skin, usingdevices having a substance transfer component (which may include, forexample, one or more microneedles and/or other skin insertion objects).The device may also contain, in some embodiments, a storage chamberhaving an internal pressure less than atmospheric pressure prior toreceiving blood or other bodily fluids. In some cases, the device maypierce the skin of the subject, and fluid can then be delivered and/orreceived from the subject. The subject is usually human, althoughnon-human subjects may be used in certain instances, for instance, othermammals such as a dog, a cat, a horse, a rabbit, a cow, a pig, a sheep,a goat, a rat (e.g., Rattus Norvegicus), a mouse (e.g., Mus musculus), aguinea pig, a hamster, a primate (e.g., a monkey, a chimpanzee, ababoon, an ape, a gorilla, etc.), or the like.

In some cases, the device can be applied to the skin, and activated toreceive fluid from the subject. The device, or a portion thereof, maythen be processed to determine the fluid and/or an analyte within thefluid, alone or with an external apparatus. For example, fluid may bereceived from the device, and/or the device may contain sensors oragents able to determine the fluid and/or an analyte suspected of beingcontained in the fluid.

The inventors have appreciated that the performance of microneedles orother skin insertion objects when inserted into skin to receive fluids,or to deliver therapeutics or fluids, depends on the mechanicalstability and sharpness of the needles used, and that the force neededto insert microneedles into skin depends on the interfacial area betweenthe microneedle tip and the skin contact surface. That is, needles forsome applications should have a suitably small interfacial area toreduce the force needed to insert the needles into skin, and be strongenough to withstand the force so as to prevent breaking or bending ofthe needles. Also, on amount of fluid received or delivered via theneedles depends on the cross sectional area and number of microneedleswithin a given array, as well as the length of the needles. In someaspects of the invention, provided microneedles have a reducedinterfacial area (i.e., increased sharpness) and an increased number ofmicroneedles per unit area of an array (i.e., higher packing density).This results in microneedle arrays that penetrate the skin more easilyand reliably than other arrays and/or allow for the receiving or thedelivery of greater volumes (and/or higher flow rates) of fluid. In somecases, needles of greater length may be more easily bent or damagedduring insertion. Needles that require smaller insertion forces (due toincreased sharpness or other factors) allow needles to be formed atlonger lengths with less risk of deformation during insertion.

One aspect of the invention relates to a microneedle arrangement inwhich the microneedle, and/or an array of microneedles, has improvedpenetration, fluid transfer or other performance characteristics. In oneembodiment, a microneedle may have a point at its distal end that isformed at the intersection of at least four surfaces. Such anarrangement may provide for improved insertion characteristics, e.g.,allow the microneedle to more easily penetrate skin and/or maintain astraight trajectory when being inserted into skin or other material.This is in contrast to prior needle tip arrangements in which the needlehas a leading contact surface in the form of a line as opposed to apoint. For example, FIG. 13 shows a prior microneedle arrangement astaught in U.S. Patent Publication 20070161964 in which the microneedle 1has a penetrating portion 2 that extends upwardly at an angle relativeto a base portion 3 and has a sword-like shape with a tip 4 at a distalend of the penetrating portion 2. In this arrangement, however, thepenetrating portion 2 has flat surfaces 5 at its periphery configuredsuch that the tip 4 has a line shape at its extreme distal end. That is,the leading contact surface of the penetrating portion 2 is a lineformed by the intersection of two surfaces 5. In some cases, a line-typeleading contact surface may not be ideal, e.g., may require relativelyhigher forces to be placed on the microneedle 1 for insertion thandesired.

In contrast, FIG. 14 shows one embodiment of a microneedle having a tipwith a leading contact surface in the form of a point as opposed to aline like that in the FIG. 13 embodiment. That is, in this embodiment,the periphery of the microneedle 1 is formed having a symmetrical V-typeknife edge that extends from the base 3 along the length of thepenetrating portion 2 to the lip 4. (As used herein, “periphery” refersto at least a portion of an outer edge of the microneedle, and does notnecessarily include the entire outer edge of the microneedle.)Accordingly, the penetrating portion 2 has an approximatelyhexagon-shaped cross-section as shown in FIG. 15 (which is a lateralcross section along a line 15-15 shown in FIG. 14). As can also be seenin FIG. 15, the opposed substantially planar sides 6 of the penetratingportion 2 are interconnected by the knife edge surfaces 5, which arearranged at non-perpendicular angles to the sides 6, and are arranged atan acute angle relative to each other. Thus, when viewed from the top asshown in FIG. 16, the tip 4 has a point at its extreme distal end thatis formed at the intersection of four surfaces 5 a, 5 b, 5 c and 5 d.Having the tip 4 arranged to have a point may provide benefits, such asreduced force or friction when inserting the penetrating portion 2 intoskin or other material. Alternately, or in addition, the surfaces 5 a-5d may help maintain a straight trajectory of the tip 4 and penetratingportion 2 when inserted into skin or other material. That is, contact ofthe surfaces 5 a-5 d with skin during penetration may exert balancedforces on the penetrating portion 2 that helps to keep the tip 4traveling along a straight path. This is in contrast to an arrangementlike that in FIG. 13 where the tip 4 has no surfaces to provide balancedforces on the tip in directions generally perpendicular to the width ofthe penetrating portion 2, i.e., in directions parallel to the planes ofthe side surfaces 5 of the penetrating portion 2 at the tip 4. Thepointed tip 4 of the FIG. 14 embodiment is also in contrast to amicroneedle arrangement like that shown in FIGS. 25 and 26, in which themicroneedle has a single beveled surface 5 at its periphery. Since themicroneedle in FIG. 25 has single beveled surfaces 5 at the tip 4, thetip 4 will generally not experience balanced forces when inserted intoskin or other material. This is because the beveled surfaces 5 at thetip 4 will exert a force on the tip 4 that tends to bend the penetratingportion away from the base 3, tending to flatten the needle. Such forcescan cause the microneedle 1 to bend or break in some environments,rendering the microneedle 1 less useful for its intended function. Forexample, one of the possible consequences of bending is incompleteinsertion. Bending during insertion causes the needles to deflect awayfrom each other and results in a non-parallel arrangement between theneedles. This may, in turn, limit the insertion depth.

It should be understood that embodiments in accordance with theinvention may be configured in ways other than that shown in FIGS.14-16. For example, FIG. 17 shows a microneedle 1 arrangement having achisel-like shape as opposed to the sword-like shape in FIG. 14.However, as in the FIG. 14 embodiment, a periphery of the penetratingportion 2 has a V-type knife edge formed by surfaces 5 that are arrangedat an acute angle relative to each other and that interconnect, or join,the relatively broad, opposed planar sides 6 of the penetrating portion2. Also like the FIG. 14 embodiment, the tip 4 in FIG. 17 has a pointthat is formed at the intersection of four surfaces, i.e., the knifeedge surfaces 5. However, it should be noted that while the microneedlein FIG. 17 may experience balanced forces on the tip 4 in directionsgenerally perpendicular to the sides 6, the longer, angled surfaces 5 onthe right side of the microneedle 1 may exert forces on the penetratingportion 2 that cause the microneedle 1 to bend toward the left (as shownin FIG. 17) when being inserted into skin or other material. Otherarrangements are possible in accordance with aspects of the invention,such as forming a knife edge on a periphery of the penetrating portionin an asymmetrical way (e.g., so that the surfaces 5 have a differentwidth and/or are arranged at a different angle with respect to theplanar sides 6 of the penetrating portion), forming the knife edge so asto include more than two surfaces that interconnect the planar sides 6(e.g., each surface 5 may be arranged to be formed by two or moresurfaces), the penetrating portion 2 may be arranged to include two ormore points (e.g., the sword shaped penetrating portion 2 of FIG. 14 maybe split so that a slot extends from the tip 4 down toward the base 3,thus providing the penetrating portion 2 with two points), thepenetrating portion 2 may include one or more channels, holes, groovesor other features (e.g., such as the opening in the needle of FIG. 13 tofacilitate fluid flow), and others.

Another aspect of the invention relates to a method for forming amicroneedle, e.g., so as to include a knife edge or other multiplesurface arrangement at a periphery of the microneedle. One embodimentshown schematically in FIGS. 18 and 19 involves providing a layer ofmaterial from which one or more microneedles is to be formed. The layermay include any suitable material or combination of materials, such asmetals, polymers, ceramics, and other materials. In this illustrativeembodiment, the layer 7 is a single layer of titanium (e.g., a rollformed sheet, a sputter or vapor deposited layer, or otherwise formed),having top and bottom (opposed) substantially planar sides. (It shouldbe understood that the term “planar” as used herein refers to agenerally flat surface or region that may, in some cases, include bumps,holes or other relatively small surface irregularities. For example,chemical etching can in some environments form pits, grooves or othersurface features on a sheet of material. Thus, a planar side or surfaceneed not be completely flat and/or smooth.) In this embodiment, apattern 8 is formed on both the top and bottom surfaces of the layer 7that corresponds to at least a portion of the desired shape for themicroneedle 1 (FIG. 14). In this case, the patterns 8 have a sword-likeshape so as to form a sword shaped microneedle 1, although other shapesor configurations are possible. The pattern 8 may be formed in anysuitable way, such as by a photolithographic process includingdepositing a layer of photoresist on the layer 7, exposing thephotoresist to a suitable illumination pattern, and etching the resistto form the pattern 8 shown in FIG. 18. After providing the patterns 8,the layer 7 may be etched (e.g., by chemical etching) from one or bothsides (whether simultaneously or consecutively) to form the microneedle1 having edge surfaces 5 that form a knife edge at the periphery of themicroneedle 1. As is understood in the art, if the layer 7 is anisotropic material (or otherwise suitably formed) and the etchingprocess is likewise isotropic (i.e., equal in etch rate to alldirections), beveled surfaces 5 will be formed as shown in FIG. 19. Thisarrangement can provide a convenient way to form a knife edge around themicroneedle 1 with a suitably sharp edge and other characteristics.Moreover, the use of photolithographic processes to form themicroneedles allows for a flexibility in the shape, size and otherfeatures of the needles.

Although the pattern and etching method shown schematically in FIGS. 18and 19 can be used to form a microneedle in accordance with aspects ofthe invention, a microneedle can be formed using other techniques. Forexample, a knife edge can be formed on a microneedle using othertechniques that do not involve a pattern and/or chemical etching, suchas grinding, molding, stamping, laser etching, and others. Accordingly,aspects of the invention regarding microneedles having certain physicalfeatures are not necessarily limited in any way with respect to howthose features are formed.

Another aspect of the invention relates to an arrangement for an arrayof microneedles. In one embodiment, a plurality of microneedles may beconfigured so that the base of each microneedle is arranged at aperiphery of a closed loop that lies in a plane. The penetrating portionof each microneedle may extend at an angle away from the base and theplane of the closed loop, e.g., to form an array of needles in aring-like shape. For example, FIG. 20 shows a microneedle arrayincluding a plurality of microneedles 1 arranged in a circular arraysuch that the base 3 of each needle 1 is arranged in a periphery of aclosed loop (in this case a circle). The penetrating portions 2 of theneedles 1 all extend at an angle (e.g., a 90 degree angle) away from theplane of the closed loop. Although in this embodiment, the microneedles1 have a knife edge and other features like that shown in FIG. 14, themicroneedles 1 may be arranged in any suitable way. For example, FIG. 21shows a similar array of microneedles 1 in which the needles have adistal end and tip arranged like that in FIG. 13. In other embodiments,the microneedles may have an arrangement like that shown in FIG. 25.Thus, an array of microneedles in accordance with this aspect of theinvention is not limited with respect to how the tip or other featuresof the microneedle 1 are configured. The closed loop may be of anysuitable shape, including, but not limited to, circular, elliptical,hexagonal, rectangular, pentagonal, octagonal or other curved orirregular shape. Also, the term “closed loop” docs not require that thebases 3 of the microneedles 1 in an array be connected together in acontinuous fashion like that shown in FIGS. 20 and 21. Rather, “closedloop” is used to refer to a shape that is formed by drawing a line thatconnects the bases of the microneedles in an array to each other. Thus,for example, the array in FIG. 20 may be arranged so that the bases 3 ofthe microneedles 1 are not connected together by an annular ring asshown, but may instead be physically separate from each other. In otherembodiments, however, the array may be arranged so that the bases 3 ofthe microneedles 1 are connected together.

FIG. 22 shows schematic steps in an illustrative method for forming anarray of microneedles arranged like that in FIGS. 20 and 21. In aninitial step, a layer of material is provided, e.g., a layer of titaniumor other suitable material or combination of materials. Next, a patternis provided on one or both sides of the layer. In this embodiment, thepattern corresponds to a desired shape of the microneedles. The patternmay be formed in any suitable way, such as using a photolithographicprocess, a stamping process, or other. Next, the layer is etched, e.g.,using a chemical etch or other suitable process, to form the layer intoa desired arrangement. Etching may be performed from one or both sidesof the layer. In this embodiment, a plurality of microneedles are formedfrom the layer with each microneedle having its base arranged in aperiphery of a closed loop (in this case a circle) and with thepenetrating portions 2 of the needles 1 extending toward a center of theclosed loop. As can be seen in the third step from the left in FIG. 22,the microneedles 1 each “point” toward at least one other microneedle inthe array, and the microneedles are generally not parallel with eachother (although some microneedles may be parallel to one or moremicroneedles). Although in this embodiment the penetrating portions 2extend toward an exact center of the closed loop, the penetratingportions may generally extend toward a center of the closed loop. Forexample, if the closed loop is in the form of an ellipse, thepenetrating portions may generally extend inwardly without having all ofthe penetrating portions extending toward a precise, geometric center ofthe ellipse. In other embodiments, the penetrating portions 2 maygenerally extend away from the center of the closed loop. Lastly, thepenetrating portions 2 of the microneedles 1 may be bent upwardly fromthe plane of the base and closed loop so that the penetrating portions 2extend at an angle from the plane. In this embodiment, the penetratingportions 2 are arranged at a 90 degree angle to the plane, but otherangles may be used. For example, the penetrating portions 2 may be bentupwardly at a 45 degree angle at a point near the base 3, and then bentupwardly again another 45 degrees at an upper region so that the tip 4extends generally perpendicularly to the plane of the closed loop andthe bases 3. This arrangement may allow the tips 4 of the penetratingportions 2 to be more compliant, allowing the penetrating portions 2 tobend elastically rather than plastically when confronted with a materialthat is difficult to penetrate. In another embodiment, a 90 degree bendmay be made at a position along the length of the needle away from theplane of the base.

Arranging microneedles such that the bases of the needles are located ata periphery of a closed loop allows for an increased packing density(e.g., number of needles per unit area) than prior arrangements. In someembodiments, the packing density may be 2 microneedles per squaremillimeter or more, e.g., where the microneedle length is greater than500 microns. For example, FIG. 21 shows a plan view of a microneedlearray formed like that in FIG. 22 prior to bending the penetratingportions 2 upwardly away from the bases 3 and the common plane of thelayer in which the microneedles are initially formed. This arrangementincludes a total of 16 microneedles. In one embodiment, the microneedlesmay each be about 750 μm long and the array may have a diameter of about3 mm. In contrast, FIG. 24 shows a rectangular array of 8 microneedleseach having the same size and shape as in the FIG. 23 embodiment, i.e.,the needles are 750 μm long and are parallel to each other, and thearray has a diameter of about 3 mm. Since the FIG. 23 array has twicethe number of needles, the FIG. 23 array will have a larger capacity forfluid flow (whether total fluid volume and/or flow rate) as compared tothe FIG. 24 array while having the same overall size. Moreover, thecentral void in the FIG. 23 array (i.e., the central area containing noneedles) may provide additional benefits, such as channeling flow towarda center of the array for easier collection. In some cases, a smalldistance between microneedles may decrease ease of insertion. In somecases, it may be desirable to maintain a minimum spacing betweenmicroneedles. For example, the minimum spacing may be about 100micrometers, about 200 micrometers, about 300 micrometers, about 400micrometers, about 500 micrometers, about 600 micrometers, about 700micrometers, about 800 micrometers or about 900 micrometers. Thisminimum spacing limits the number of needles that can be arranged in aconfined area, for example, a base with a small area. In some cases, acircular configuration may maximize the number of needles that can fitin the confined area.

Aspects of the invention are not limited to microneedle arrays in whichonly a single group of microneedles are arranged with their bases at theperiphery of a closed loop. For example, an array may include two ormore groups of needles that are arranged with respect to differentclosed loops. Arrays may include a plurality of groups of needles. FIG.27 shows an illustrative embodiment that includes a first group ofmicroneedles 1 arranged in an inner pattern (in this case a circulararrangement) and a second group of microneedles 1 arranged in an outerpattern (also a circular pattern in this embodiment. Other arrangementswill occur to those of skill in the art. For example, the closed loopsfor concentric patterns like that in FIG. 27 may have different sizes orshapes, such as a first inner group of needles arranged with respect toa closed loop in a pentagonal shape and a second outer group of needlesarranged with respect to a closed loop in a hexagonal shape. Moreover,the centers of the closed loops need not be coincident, but instead maybe offset from each other.

In yet other embodiments, an array may include three or more closedloops of microneedles, such as a larger closed loop of microneedles thatsurrounds two smaller closed loops of microneedles. The closed loopsneed not be “concentric” in the sense that a smallest closed loop iscontained within a medium sized closed loop, which is in turn containedwithin a larger closed loop and soon. Instead, for example, two smallerclosed loops may be adjacent each other and contained within a largerclosed loop. In some illustrative embodiments, however, the closed loopsare concentric circles. In some embodiments, a needle arrangement mayinclude a plurality of these pairs of closed loops.

The invention, in one set of embodiments, involves the determination ofa condition of a subject. Bodily fluids and/or other material associatedwith the skin may be analyzed, for instance, as an indication of a past,present and/or future condition of the subject, or to determineconditions that are external to the subject. Determination may occur,for instance, visually, tactilely, by odor, via instrumentation, etc. Inone aspect, accordingly, the present invention is generally directed tovarious devices for delivering and/or receiving blood, or other bodilyfluids, from the skin and/or from beneath the skin of a subject.Accordingly, in the description that follows, the discussion of blood isby way of example only, and in other embodiments, other fluids may bereceived from the skin in addition to and/or instead of blood.

In one set of embodiments, the device includes a substance transfercomponent able to deliver to or receive fluid from the subject. As usedherein, “substance transfer component” is any component or combinationof components that facilitates movement of a substance or a fluid fromone portion of the device to another, and/or from the device to thesubject or vice versa. The substance transfer component may include anopening of any size and/or geometry that is constructed to receive fluidinto the device. For example, an opening of a substance transfercomponent may lie in a two-dimensional plane or the opening may includea three-dimensional cavity, hole, groove, slit, etc. In someembodiments, the substance transfer component may also include one ormore microneedles or other skin insertion objects, arranged to causefluid to be released from the subject, e.g., by piercing the skin of asubject. In some embodiments, if fluid may partially or fully fill anenclosure surrounding a skin insertion object or other object, then theenclosure can define at least part of a substance transfer component. Asubstance transfer component may include any other suitable fluidtransporter or flow activator. Other components including partially orfully enclosed channels, microfluidic channels, tubes, wicking members,vacuum containers, etc. can be, or be a part of, a substance transfercomponent.

If needles or microneedles are used, they may be solid or hollow, i.e.,blood or other fluid may travel in and/or around the needles ormicroneedles into or from the device. In some cases, the needles ormicroneedles may also be removed from the subject, e.g., after insertioninto the skin, for example, to increase the flow of blood or otherfluids from the subject. In one set of embodiments, the substancetransfer component includes solid needles that are removed from the skinand a cup or channel to direct the flow of blood or other bodily fluids.

It should be noted that a skin insertion object or other flow activatorneed not be included with all embodiments as the device may notnecessarily employ a mechanism for causing fluid release from thesubject. For instance, the device may receive fluid that has alreadybeen released due to another cause, such as a cut or an abrasion, fluidrelease due to a separate and independent device, such as a separatelancet, an open fluid access such as during a surgical operation, and soon. Additionally, fluid may be introduced into the device via urination,spilling, pouring fluid into the device, etc. If included, a skininsertion object or other substance transfer component may physicallypenetrate, pierce, and/or or abrade, chemically peel, corrode and/orirritate, release and/or produce electromagnetic, acoustic or otherwaves, other otherwise operate to cause fluid release from a subject.The substance transfer component may include a moveable mechanism, e.g.,to move a needle, or may not require movement to function. For example,the substance transfer component may include a jet injector or a“hypospray” that delivers fluid under pressure to a subject, a pneumaticsystem that delivers and/or receives fluid, a hygroscopic agent thatadsorbs or absorbs fluid, a reverse iontophoresis system, a transducerthat emits ultrasonic waves, or thermal, radiofrequency and/or laserenergy, and so on, any of which need not necessarily require movement ofan element to cause fluid release from a subject.

In some aspects, the device may include a support structure, such as ahousing. The housing may be used, as discussed herein, for applying thesubstance transfer component to the surface of the skin of the subject,e.g., so that fluid may be delivered and/or received from the skin ofthe subject. In some cases, the housing may immobilize the substancetransfer component such that the substance transfer component cannotmove relative to the housing; in other cases, however, the substancetransfer component, or a portion thereof, may be able to move relativeto the housing. In one embodiment, as a non-limiting example, thesubstance transfer component is immobilized relative to the housing, andthe deployment actuator is positioned within the device such thatapplication of the device to the skin causes at least a portion of thesubstance transfer component to pierce the skin of the subject. In somecases, as previously discussed, the housing encloses a deploymentactuator.

In some embodiments, the deployment actuator, or a portion of thedeployment actuator, may move from a first position to a secondposition. For example, the first position may be one where thedeployment actuator has attached thereto a substance transfer componentthat is not in contact with the skin (e.g., a skin insertion object ofthe substance transfer component may be contained within a recess of thesubstance transfer component), while the second position of thedeployment actuator may be one where the substance transfer componentdoes contact the skin, e.g., to pierce the skin. The deployment actuatormay be moved using any suitable technique, e.g., manually, mechanically,electromagnetically, using a servo mechanism, or the like. In one set ofembodiments, for example, the deployment actuator may be moved from afirst position to a second position by pushing a button on the device,which causes the deployment actuator to move (either directly, orthrough a mechanism linking the button with the deployment actuator).Other mechanisms (e.g., dials, levers, sliders, etc., as discussedherein) may be used in conjunction of or instead of a button. In anotherset of embodiments, the deployment actuator may be moved from a firstposition to a second position automatically, for example, uponactivation by a computer, upon remote activation, after a period of timehas elapsed, or the like. For example, in one embodiment, a servoconnected to the deployment actuator is activated electronically, movingthe deployment actuator from the first position to the second position.In some cases, the deployment actuator may include a triggeringmechanism that initiates deployment.

In some cases, the deployment actuator and/or the substance transfercomponent may also be moved from the second position to the firstposition for some other position). For example, after fluid has beendelivered and/or received from the skin, e.g., using a substancetransfer component, the deployment actuator may be moved, which may movethe substance transfer component away from contact with the skin. Thedeployment actuator may be moved from the second position to the firstposition using any suitable technique, including those described above,and the technique for moving the deployment actuator from the secondposition to the first position may be the same or different as thatmoving the deployment actuator from the first position to the secondposition.

In some cases, the device may be able to draw skin towards the substancetransfer component. For example, in one set of embodiments, the devicemay include a vacuum interface or region. The interface or region may beconnected with a vacuum source (external and/or internal to the device),and when a vacuum is applied, skin may be drawn towards the device,e.g., for contact with a substance transfer component, such as one ormore needles or microneedles.

In one set of embodiments, the device includes a deployment actuatorable to drive a substance transfer component into the skin, e.g., sothat the device can receive a fluid from the skin of a subject, and/orso that the substance transfer component can deliver a substance to asubject, e.g. deliver a substance to the skin and/or to a locationbeneath the skin of a subject. The deployment actuator may be astructure that can be deformed using unaided force (e.g., by a humanpushing the structure), or other forces (e.g., electrically-appliedforces, mechanical interactions or the like), but is able to restore itsoriginal shape after the force is removed or at least partially reduced.For example, the structure may restore its original shape spontaneously,or some action (e.g., heating) may be needed to restore the structure toits original shape. In one set of embodiments, the deployment actuatormay include a flexible concave member or a reversibly deformablestructure that is moveable between a first configuration and a secondconfiguration. The deployment actuator may be formed out a suitableelastic material, in some cases. For instance, the structure may beformed from a plastic, a polymer, a metal, etc. In one set ofembodiments, the structure may have a concave or convex shape. Forinstance, the edges of the structure may be put under compressive stresssuch that the structure “bows” out to form a concave or convex shape. Aperson pushing against the concave or convex shape may deform thestructure, but after the person stops pushing on the structure, thestructure may be able to return to its original concave or convex shape,e.g., spontaneously or with the aid of other forces as previouslydiscussed. In some cases, the device may be bistable, i.e., having twodifferent positions in which the device is stable.

An example of a deployment actuator is now illustrated with respect toFIG. 10. In FIG. 10A, structure 700 has a generally concave shape, andis positioned on the surface of skin 710. Structure 700 also includes asubstance transfer component 720 for insertion into the skin. In FIG.10B, a person (indicated by finger 705) pushes onto structure 700,deforming at least a portion of the structure and thereby forcing asubstance transfer component 720 into at least a portion of the skin. InFIG. 10C, after the person releases structure 700, the structure isallowed to return to its original position, e.g., spontaneously, liftingsubstance transfer component 720 out of the skin. In some cases, e.g.,if the substance transfer component includes needles or other skininsertion objects that are sufficiently large or long, blood or otherfluids 750 may come out of the skin through the holes created by theneedles, and optionally the fluid may be collected by the device forlater storage and/or use, as discussed herein.

As another example, referring now to FIG. 11, a device 1100 isillustrated schematically in which a substance transfer component isdriven by a deployment actuator. In FIG. 11, device 1100 includes ahousing 1102 defining a plurality of chambers and channels. In otherembodiments (not shown) a plurality of components that can be separablefrom and attachable to each other (e.g., modular components) cantogether define the device and together define a series of channels andcompartments necessary for device function. See. e.g., U.S. patentapplication Ser. No. 12/716,233, filed Mar. 2, 2010, entitled “Systemsand Methods for Creating and Using Suction Blisters or Other PooledRegions of Fluid within the Skin,” by Levinson, et al.; U.S. patentapplication Ser. No. 12/716,226, filed Mar. 2, 2010, entitled“Techniques and Devices Associated with Blood Sampling,” by Levinson, etal.; or U.S. patent application Ser. No. 12/716,229, filed Mar. 2, 2010,entitled “Devices and Techniques Associated with Diagnostics, Therapies,and Other Applications, Including Skin-Associated Applications,” byBernstein, et al., each incorporated herein by reference.

In the specific device illustrated, device 1100 includes a surface 1104for positioning the device proximate the skin of a subject during use.Where desired in certain embodiments, the device can include an adhesivelayer 1106 where the adhesive is selected to be suitable for retainingthe device in a relatively fixed position relative to the skin duringuse, but may allow for relatively easy removal of the device from theskin following use. Specific non-limiting examples of adhesives arediscussed below. The adhesive also can be selected to assist inmaintaining a vacuum within portions of the device proximate the skin aswill be understood.

In FIG. 11, device 1100 includes a substance transfer component 1108.The substance transfer component may be or include, for example, a skininsertion object or other suitable object as discussed herein. Specificnon-limiting examples include needles or microneedles, e.g., as shown inFIG. 11. The substance transfer component can be or include, asdescribed elsewhere herein and in other documents incorporated herein byreference, any of a variety of components able to receive a substancefrom the skin and/or from beneath the skin of a subject, and or delivera substance to the skin and/or to a location beneath the skin of thesubject. For example, the substance transfer component may include oneor more needles and/or microneedles, a hygroscopic agent, a cutter orother piercing element, an electrically-assisted system, or the like. Inthe specific device illustrated, substance transfer component 1108includes an array of skin insertion objects such as solid or hollowmicroneedles. In one set of embodiments, substance transfer component1108 is selected to have a particular size and profile for a particularuse. For example, the substance transfer component may include an arrayof skin insertion objects which, in the device illustrated, emanate froma base 1110 which will be described further below.

In certain embodiments, a plurality of skin insertion objects of thesubstance transfer component 1108 and are relatively small, and arerelatively completely driven into the skin. The skin insertion objectsmay be positioned to address the skin of the subject, each protrudingfrom a base and defining a length from the base, and are able to beinserted into or through the skin to a depth essentially equal to theirlength but are prevented, by the base, from inserting at a depth greaterthan their length. In some embodiments, the plurality of skin insertionobjects have an average length (measured from the base) of no more thanabout 1,000 microns or more than about 2,000 microns, although lengthscan differ between individual skin insertion objects. In one set ofembodiments, the skin insertion objects are of relatively uniformlength, together defining an average length and each differing from theaverage length by no more than about 50%, about 40%, about 30%, about10%, or about 5%. The average length of the skin insertion objects, inother embodiments, are no more than about 1,500 microns, no more thanabout 1,000 microns, no more than about 900 microns, no more than about800 microns, no more than about 750 microns, no more than about 600microns, no more than about 500 microns, no more than about 400 microns,or no more than about 350 microns. In some embodiments, a deploymentactuator as discussed herein is provided that is able to move the skininsertion object from a fully pre-deployed position to a fully deployedposition with a force sufficient to insert the plurality of skininsertion object into or through the skin to an average insertion depthof at least about 50% the average length of the plurality of skininsertion objects. In other embodiments, the deployment actuator is ableto insert the plurality of skin insertion objects to an averageinsertion depth of at least about 55%, at least about 60%, at leastabout 65%, at least about 70%, at least about 75%, at least about 80%,at least about 85%, at least about 90%, at least about 92%, about 94%,about 96%, or about 98% of the average length of the plurality of skininsertion objects.

In the device illustrated, the skin insertion objects of the substancetransfer component 1108 are mounted on a flexible structure 1112 which,as illustrated, is maintained relatively rigidly through various aspectsof the device but which mounts substance transfer component 1108flexibly for up/down movement relative to the skin. Flexible structure1112 can be a membrane, a single or multi-layer structure selected fromvarious polymers or the like to provide sufficient properties such asany combination of flexibility, elasticity, gas permeability orimpermeability, fluid permeability or impermeability, or the like fordesired operation. Portions of flexible structure 1112, skin insertionobjects t 1108, and other interior walls of the device define a region1114 which allows for movement of skin insertion objects 1108 relativeto the skin for delivery of a substance to and/or receiving of asubstance from the skin or beneath the skin, and, where a substance isreceived from the skin or from beneath the skin, region 1114 can serveas a reservoir for introduction of the substance into the device. Wherea vacuum is used to receive a substance from the subject (as in theembodiment illustrated in FIG. 11), region 1114, when positioned againstthe skin, can expose vacuum to that portion of the skin proximatesurface 1104 of the device and abutting the chamber.

Device 1100 also includes a transfer component actuator 1116 which, asillustrated, includes a proximate portion 1118 which can be addressed bya user of the device (who may be the same or different from the subjectthe device is administered to) and a distal portion 1120 for addressingskin insertion objects 1108 via flexible structure 1112. Proximalportion 1118 and distal portion 1120 are, in the device illustrated,opposite ends of a single component but, as would be understood by thoseof ordinary skill in the art, the actuator can include a plurality ofindividual components operably linked in any way necessary to performactuation as will be described.

As will be understood, FIG. 11 is a cross-section of a deviceillustrating various components and channels within the device. As willalso be understood by those of ordinary skill in the art, differentarrangements of devices and channels are contemplated herein so long asthe purpose of the device described herein is met. In this figure,device actuator 1116 is directly connected to or otherwise operablylinked to a deployment actuator 1122 which, in the device illustrated,is in the form of a “snap dome,” the function and use of which will bedescribed below. The snap dome in this figure has an approximatelycircular profile. The structure may define an interior and a peripherywhich, if not circular, may include a plurality of tabs, protrusions, orthe like sufficient for support of structure 1122 within the device. Asillustrated, a plurality of tabs (or the essentially circular perimeterof) the device are supported within holders 1124, and the center, snapdome portion of the device is operably linked to device actuator 1116,such that movement of the central portion of snap dome 1122 and theperiphery of the snap dome can be controlled independently of eachother. Holders 1124 are directly connected to or otherwise operablylinked to a retraction actuator 1126 which, in the device illustrated,can be a ring-shaped structure positioned under and supporting holders1124. Holders 1124 can be individual holders and/or a ring-likestructure surrounding the periphery of snap dome 1122. A series of one,two, or more support members (e.g., 1130) are positioned near the top ofdevice 1100 and serve to define a series of channels for sample flow,vacuum control, or the like as will be described.

Turning now to channels defined within the device, as described above,region 1114, when the device is positioned against skin, can serve toexpose a portion of the skin defined by the periphery of the region to avacuum, to substance transfer component 1108 as it moves toward and/oraway from the skin, and/or to transfer a substance from or to thesubject. Region 1114 can house a substance for transfer to the subject,to the form of a pharmaceutical composition or the like, optionallyloaded on skin insertion objects 1108. Where blood and/or interstitialfluid is drawn from a subject, region 1114 can serve to introduce thesubstance into the device from the subject.

A channel 1132 connects region 1114 to other portions of the device inthis example. Channel 1132 can be used to deliver a substance to region1114 for transfer to a subject, or for application of a vacuum to region1114, and/or for receiving of a substance from a subject. The remainderof the description of device 1100 will be made within the context ofreceiving a substance such as blood and/or interstitial fluid from asubject, but it is to be understood that substances can also bedelivered via various channels. Channel 1132 typically emanates in onedirection from region 1114 although a plurality of channels can emanatefrom the region, arranged radially or otherwise, relative to the centerof the device. In device 1100, channel 1132 first passes laterally fromthe center of the device and then upwardly where, near the top of thedevice, it can, optionally, include one wall defining a window 1134through which a user of the device can observe transfer of a substance,or through which analysis of a substance may occur. It can also itselfdefine a reservoir, in whole or in part, or be connected to an internalor an external reservoir for maintaining, storing, and/or transferring asubstance drawn from a subject. As shown here, it can be connected to asubstance collection reservoir 1136 which, as illustrated, is adisc-shaped reservoir formed in the device housing and surrounding thecenter of the device including device actuator 1116 and relatedcomponents. Device 1100, illustrated as one example of devices providedby the invention, includes a vacuum chamber for applying a vacuumproximate the skin of a subject for receiving a substance from the skin.As illustrated, vacuum chamber 1138 is positioned in a central portionof the device surrounding device actuator 1116, although it can beprovided anywhere in or proximate the device. The vacuum chamber can beevacuated to an appropriate level just prior to use, or the device canbe pre-packaged under vacuum as described elsewhere herein. Asillustrated, vacuum chamber 1138 is in fluid communication withsubstance collection reservoir 1136 but, in its initial state and priorto use, a membrane or other component, such as support member 1128,separates channel 1132 connecting it to region 1102. In the deviceillustrated, a vacuum actuation component 1140 can be actuated topuncture the membrane or other component (e.g., 1128) and therebyconnect vacuum chamber 1138 with channel 1132, at an appropriate timeduring use of the device. In other embodiments, device actuator 1116 andvacuum actuation component 1140 can be combined into a single button oroperably linked so that only one operation is needed to actuate both theskin insertion objects and the vacuum.

Deployment actuator (or, as shown, a snap dome) 1122 can be provided ina variety of forms including a monostable or bistable configuration. Inthe embodiment illustrated, a bistable configuration is illustratedincluding first and second low energy or stable configurations separatedby a relatively high energy or unstable configuration. As shown, thedeployment actuator 1122 is shown in a “cocked” or pre-deployedposition.

The deployment actuator may be formed from any suitable material, forexample, a metal such as stainless steel (e.g., 301, 301LN, 304, 304L,304LN, 304H, 305, 312, 321, 321H, 316, 316L, 316LN, 316Ti, 317L, 409,410, 430, 440A, 440B, 440C, 440F, 904L), carbon steel, spring steel,spring brass, phosphor bronze, beryllium copper, titanium, titaniumalloy steels, chrome vanadium, nickel alloy steels (e.g., Monel 400,Monel K 500, Inconel 600, Inconel 718, Inconel x 750, etc.), a polymer(e.g., polyvinylchloride, polypropylene, polycarbonate etc.), acomposite or a laminate (e.g., comprising fiberglass, carbon fiber,bamboo, Kevlar, etc.), or the like. The deployment actuator may be ofany shape and/or size. For example, the deployment actuator may have agenerally domed shape (e.g., as in a snap dome), and be circular (nolegs), or the deployment actuator may have other shapes, e.g., oblong,triangular (3 legs), square (4 legs), pentagonal (5 legs), hexagonal (6legs), spiderlegged, starlike, clover-shaped (with any number of lobes,e.g., 2, 3, 4, 5, etc.), or the like. The deployment actuator may have,in some embodiments, a hole, dimple, or button in the middle. Thedeployment actuator may also have a serrated disc or a wave shape. Insome cases, the substance transfer component may be mounted on thedeployment actuator. In other cases, however, the substance transfercomponent is mounted on a separate structure which is driven or actuatedupon movement of the deployment actuator.

In one set of embodiments, the deployment actuator is not planar, andhas a portion that can be in a first position (a “cocked” orpre-deployed position) or a second position (a “fired” or deployedposition), optionally separated by a relatively high energyconfiguration. In some cases, the pre-deployed position may be at ahigher energy level than the deployed position. In some cases, both thefirst position and the second position are stable (i.e., the structureis bistable), although conversion between the first position and thesecond position requires the structure to proceed through an unstableconfiguration.

In some cases, surprisingly, the distance or separation between thefirst position and the second position is relatively small. Suchdistances or separations may be achieved using snap domes or otherconfigurations such as those described herein, in contrast to springs orother devices which require longer translational or other movements. Forexample, the perpendicular distance (i.e., in a direction away from theskin) in the deployment actuator between the top of the structure andthe bottom of the structure (excluding the substance transfer component)when the device containing the structure is placed on the skin of asubject may be no more than about 5 mm, no more than about 4 mm, no morethan about 3 mm, no more than about 2 mm, no more than about 1 mm insome cases, no more than about 0.8 mm, no more than about 0.5 mm, or nomore than about 0.3 mm. In one set of embodiments, the distance isbetween about 0.3 mm and about 1.5 mm. In another set of embodiments,the deployment actuator may have a greatest lateral dimension (parallelto the skin) when the device containing the structure is placed on theskin of a subject of no more than about 50 mm, no more than about 40 mm,no more than about 30 mm, no more than about 25 mm, no more than about20 mm, no more than about 15 mm, no more than about 5 mm, no more thanabout 4 mm, no more than about 3 mm, no more than about 2 mm, no morethan about 1 mm in some cases, no more than about 0.8 mm, no more thanabout 0.5 mm, or no more than about 0.3 mm. In one set of embodiments,the distance is between about 0.3 mm and about 1.5 mm.

Use of device 1100 will now be described in the context of receiving asubstance such as blood from a subject. Device 1100 is placed againstthe skin of a subject such that at least a portion of surface 1104contacts the skin. Prior to use, a cover member (not shown) can coversurface 1104 of the device and can cover region 1114, to protect surface1104 and region 1114 from contaminants, etc. optionally maintaining theinterior of the device in a sterile condition. The cover can be peeledof or otherwise removed from the device, and the device placed againstthe skin, optionally adhering to the skin. Vacuum actuation component1140 can be actuated to expose channel 1132 and region 1114 to vacuum atany time, including before, simultaneously, or after actuation ofsubstance transfer component 1108. In one arrangement, vacuum actuationcomponent 1140 is actuated to apply vacation to region 1114 prior toactuation to substance transfer component 1108, thereby to create avacuum against the skin proximate region 1114 prior to use. Actuation ofdevice actuator 1116 can take place before or after deployment ofvacuum.

When device actuator 1116 is actuated by a user (e.g., when proximalportion 1118 is depressed downwardly as shown in the figure), distalportion 1120 engages skin insertion objects 1108 (optionally viaflexible structure 1112) to drive it toward the skin. In someembodiments, foil 1128 is first broken, then retraction actuator 1126 iscompressed, then retraction actuator 1126 is broken, before flexiblestructure 1112 is stretched and the deployment actuator 1122 of thedevice fires or is actuated. Membranes or other members 1112, 1128, or1130 may have, in some cases, sufficient flexibility and/or elasticityto allow actuator 1116 to drive skin insertion objects 1108 sufficientlydistally (downwardly, as shown) to engage the skin of the subject andcarry out the desired function of the device. Various gaskets, bearings,or membranes as shown can be used for this function. Where supportmember 1128 is a foil or the like used for the purpose of initiallyseparating vacuum reservoir 1138 from channel 1132 (e.g., prior to use),when device actuator 1116 is moved downwardly, vacuum actuationcomponent 1140 may rupture support member 1128 proximate actuator 1116,or flexibly deform as need be, so long at member 1130 (or anothercomponent) serves to allow device actuator 1116 to move slidably withinthe device white maintaining sufficient vacuum in vacuum reservoir 1138and related channels for use of the device.

When skin insertion objects 1108 engage the skin of the subject andfacilitates receiving of a substance from the skin and/or from beneaththe skin of the subject, a vacuum can draw the substance into region1114, through channel or channels 1132, and into substance collectionreservoir 1136. In this process, device actuator 1116 first urgesdeployment actuator 1122 from its first stable configuration to arelatively unstable configuration and beyond that point, at which pointthe deployment actuator 1122 rapidly moves to a second stableconfiguration associated with downward driving of device actuator 1116to quickly drive access substance transfer component 1108 proximate theskin.

After that point, if it is desirable for access substance transfercomponent 1108 to be received from the skin, then a variety oftechniques can be used to do so. In the device illustrated, retractionactuator 1126 drives holder 1124 upwardly, retracting structure 1122 anddevice actuator 1116 from substance transfer component 1108. At thatpoint, device actuator 1116 can be operably linked to transfer component1108 and retract the transfer component, or it can move freely relativeto substance transfer component 1108, whereby flexible structure 1112(e.g., an elastic membrane) or other component can retract substancetransfer component 1108 from the skin. The retraction actuator 1126 mayinclude any suitable retraction component. Again, in the deviceillustrated, retraction actuator 1126 can itself be a reversiblydeformable structure such as a leaf spring, coil spring, foam, or thelike. During use, when device actuator 1116 is driven downwardly,retraction actuator 1126 is first compressed and, depending upon thesize and arrangement of components 1126, 1124, 1122, 1116 and 1108,during compression, substance transfer component 1108 can be drivendownwardly to some extent. At the point at which retraction actuator1126 is compressed and provides a sufficient resistance force,deployment actuator 1122 can be urged from its first configurationthrough an unstable configuration and can return to its secondconfiguration, driving substance transfer component 1108 against theskin. Then, upon release of user pressure (or other actuation, which canbe automatic) from actuator 1116, retraction actuator 1126 can expandand, with structure 1122 optionally remaining in its second,downwardly-driven low-energy configuration, actuator 1116 can beretracted and substance transfer component 1108 retracted from the skin.

Referring now to FIGS. 12A and 12B, device 1150 is illustratedschematically. Device 1150 is similar to and can be consideredessentially identical to device 1100 in all aspects other than thosedescribed here with respect to FIGS. 12A and 12B. As such, the readerwill observe that not all components are provided, although othercomponents similar to those of device 1100 can exist. One way in whichdevice 1150 differs from device 1100 is that in device 1150, in thepre-deployment or post-deployment retracted configuration, membrane 1112is drawn proximally (upwardly) as illustrated in FIG. 12B. Membrane 1112is in a less-stressed lower-energy configuration as shown in FIG. 12Awhen retraction actuator 1126 is compressed and substance transfercomponent 1108 is driven proximate the skin. Devices 1100, 1150, andother similar devices are one way to enact a deployment actuator thatcan move a substance transfer component 1108 relative to the skin inparticularly advantageous ways. Examples of deployment actuatorsinclude, in addition to the examples shown in FIGS. 11 and 12, blastingcaps, explosives, other chemical reactions, solenoids or otherelectrical interactions, pneumatics (e.g., compressed air), otherthermal interactions or mechanical interactions, or the like.

In one set of embodiments, the deployment actuator may move substancetransfer component 1108 from a fully pre-deployed position (e.g., asshown in FIG. 11) to a fully deployed position in which substancetransfer component 1108 is fully engaged with the skin, in a shortperiod of time. In one embodiment, that period of time is less thanabout 0.01 seconds, and in other embodiments, less than about 0.009seconds, less than about 0.008 seconds, less than about 0.007 seconds,less than about 0.006 seconds, less than about 0.005 seconds, less thanabout 0.004 seconds, less than about 0.003 seconds, less than about0.002 seconds, less than about 0.001 seconds, less than about 0.0005seconds, less than about 0.00025, or less than about 0.0001 seconds.

In some embodiments, the distance between the fully pre-deployedposition and the fully deployed position is no more than about 1.000microns, no more than about 2,500 microns, or no more than about 5,000microns.

In another embodiment, substance transfer component 1108 moves quicklyrelative to skin during deployment via the deployment actuator, reachinga speed of at least about 4 m/s, at least about 5 m/s, at least about 6m/s, at least about 7 m/s, at least about 8 m/s, at least about 10 m/s,at least about 12 m/s, at least about 15 m/s, or at least about 20 m/satthe point at which substance transfer component 1108 first touches theskin during deployment.

In some cases, substance transfer component 1108 achieves relativelyhigh accelerations due to the deployment actuator. For example, in somecases, the deployment actuator can produce average accelerations (e.g.,average acceleration from start of movement to a position where asubstance transfer component first contacts a subject) of at least about4 m/s2, about 6 m/s2, about 8 m/s2, about 10 m/s2, about 12 m/s2, about15 m/s2, or about 20 m/s2, at least about 30 m/s2, at least about 50m/s2, at least about 100 m/s2, at least about 300 m/s2, at least about500 m/s2, at least about 1,000 m/s2, at least about 3,000 m/s2, of leastabout 5,000 m/s2, at least about 10,000 m/s2, at least about 30,000m/s2, at least about 50,000 m/s2, at least about 60,000 m/s2, at leastabout 70,000 m/s2, at least about 100,000 m/s2, at least about 200,000m/s2, or at least about 300,000 m/s2. In some cases, the deploymentactuator can produce instantaneous accelerations of at least about 4m/s2, about 6 m/s2, about 8 m/s2, about 10 m/s2, about 12 m/s2, about 15m/s2, or about 20 m/s2, at least about 30 m/s2, at least about 50 m/s2,at least about 100 m/s2, at least about 300 m/s2, at least about 500m/s2, at least about 1,000 m/s2, at least about 3,000 m/s2, at leastabout 5,000 m/s2, at least about 10,000 m/s2, at least about 30,000m/s2, at least about 50,000 m/s2, at least about 60,000 m/s2, at leastabout 70,000 m/s2, at least about 80,000 m/s2, at least about 80,000m/s2, at least about 100,000 m/s2, at least about 200,000 m/s2, or atleast about 300,000 m/s2.

Average acceleration is used to mean the rate of change of velocity overthe entire time period from the pre-deployed position to the deployedposition, and instantaneous acceleration is used to mean theacceleration of a specific point in time during the time period. Theaverage acceleration and the instantaneous accelerations may bedetermined using high-speed imaging analysis. High speed imaging is usedto capture a sequence of video frames with very short time steps betweenframes. In one example, the time step between frames may be 66microseconds, although other time steps are possible depending onimaging equipment capability and/or the total capture time. Each videoframe captures the position of a moving object at a specific moment intime. Using this data, position as a function of time may be plotted. Anequation that is fit to this data approximates position as a function oftime. The second derivative of the position equation is an equation forinstantaneous acceleration as a function of time. The accelerationequation can then be used to calculate the instantaneous acceleration atany given point in time.

In some embodiments, the substance transfer component 1108 isaccelerated for relatively short periods of time, e.g., less than about1 second, less than about 300 milliseconds, less than about 100milliseconds, less than about 30 milliseconds, less than about 10milliseconds, less than about 3 milliseconds, or less than about 1millisecond, and/or over relatively short distances, e.g., less thanabout 5 millimeters, less than about 4 millimeters, less than about 3millimeters, less than about 2 millimeters, less than about 1millimeter, less than about 800 micrometers, less than 600 micrometer,less than 500 micrometers, less than 400 micrometers, less than about300 micrometers, less than about 200 micrometers, less than about 100micrometers, less than about 50 micrometers, etc. Significant forces canbe applied to substance transfer component 1108 as it moves relative tothe skin via the deployment actuator. In another set of embodiments,substance transfer component 1108, at the point at which it firstcontacts the skin, is driven by a force created at least in part by thedeployment actuator of at least about 6 micronewtons, about 8micronewtons, about 10 micronewtons, about 12 micronewtons, or about 15micronewtons.

Significant forces can be applied to substance transfer component 1108as it moves relative to the skin via the deployment actuator. In anotherset of embodiments, substance transfer component 1108, at the point atwhich it first contacts the skin, is driven by a force created at leastin part by the deployment actuator of at least about 6 micronewtons,about 8 micronewtons, about 10 micronewtons, about 12 micronewtons, orabout 15 micronewtons.

In another set of embodiments, substance transfer component 1108 appliesa pressure to the skin, during deployment caused by the deploymentactuator, of at least about 100 N/m2, at least about 300 N/m2, at leastabout 1,000 N/m2, at least about 3,000 N/m2, etc. In force assessment,the area can be measured as the area of skin displaced by the transfercomponent at full deployment, e.g., the area of the skin ruptured by thetotal of the cross sectional area of all substance transfer componentsinserted into the skin, at the top surface of the skin.

In some cases, the substance transfer component is forced into the skinvia the deployment actuator with a force sufficient to insert thesubstance transfer component into or through the skin to an averagedepth of at least about 60% of the substance transfer component (or theaverage length of the substance transfer components, if more than one isused, e.g., as in an array of microneedles). In some cases, the depth isat least about 65%, at least about 70%, at least about 75%, at leastabout 80%, at least about 85%, at least about 90%, or at least about 95%of the substance transfer component, e.g., the length of the needle orthe microneedle inserted into the skin.

Devices of the invention can provide significant advantage in someembodiments. For example, deployment actuators able to move substancetransfer components in short time periods, and/or at high velocities,and/or with high forces, and/or with high pressure, and/or driverelatively short substance transfer components such as skin insertionobjects or microneedles relatively deeply into the skin and/or throughthe skin, and/or any combination of the above can provide significantadvantage In some embodiments, these features can provide better controlof substance delivery or receipt. Better mechanical stability can beprovided in some cases by shorter substance transfer components (e.g.,bending and/or buckling can be avoided) and relatively shorter substancetransfer components, designed to be driven relatively completely (forexample, through nearly all of their entire length) into the skin mayoffer better control of penetration in some embodiments. If bettercontrol of penetration can be achieved, better delivery or receiving canalso be achieved in some cases, for example, resulting in less pain oressentially painless deployment.

Moreover, if substance transfer components are used to deliver asubstance such as a pharmaceutical composition into or through the skin,more precise delivery can be provided, according to certain embodiments.With better, precise control over depth of insertion of the substancetransfer components (e.g., by using devices designed to insert thesubstance transfer components essentially fully), and/or the substancetransfer components contain and/or are coated with a pharmaceuticalcomposition, then more control exists over the amount of pharmaceuticalsubstance inserted into the skin by the substance transfer components,in some embodiments. Furthermore, quick and/or high velocity, and/orhigh force and/or pressure application of skin insertion objects to theskin may in certain embodiments result in lower pain or painlessdeployment.

According to one set of embodiments, many devices as discussed hereinuse various techniques for delivering and/or receiving fluid, forexample, in connection with substance transfer components, skininsertion objects, or the like. For example, one or more needles and/ormicroneedles, a hygroscopic agent, a cutter or other piercing element,an electrically-assisted system, or the like may be used in conjunctionwith a snap dome or other device as described above. Additional examplesof such techniques are described herein and/or in the applicationsincorporated herein. It is to be understood that, generally, fluids maybe delivered and/or received in a variety of ways, and various systemsand methods for delivering and/or receiving fluid from the skin arediscussed below and/or in the applications incorporated herein. In someembodiments, for example, techniques for piercing or altering thesurface of the skin to transport a fluid are discussed, for example,using a needle such as a hypodermic needle or microneedles, chemicalsapplied to the skin (e.g., penetration enhancers), jet injectors orother techniques such as those discussed below, etc.

As an example, in one embodiment, a needle such as a hypodermic needlecan be used to deliver and/or receive fluid to or from the skin.Hypodermic needles are well-known to those of ordinary skill in the art,and can be obtained commercially with a range of needle gauges. Forexample, the needle may be in the 20-30 gauge range, or the needle maybe 32 gauge, 33 gauge, 34 gauge, etc.

If needles are present, the needles may be of any suitable size andlength, and may be solid or hollow. The needles may have any suitablecross-section (e.g., perpendicular to the direction of penetration), forexample, circular, square, oval, elliptical, rectangular, roundedrectangle, triangular, polygonal, hexagonal, irregular, etc. Forexample, the needle may have a length of less than about 5 mm, less thanabout 4 mm, less than about 3 mm, less than about 2 mm, less than about1 mm, less than about 800 micrometers, less than 600 micrometers, lessthan 500 micrometers, less than 400 micrometers, less than about 300micrometers, less than about 200 micrometers, less than about 175micrometers, less than about 150 micrometers, less than about 125micrometers, less than about 100 micrometers, less than about 75micrometers, less than about 50micrometers, etc. The needle may alsohave a largest cross-sectional dimension of less than about 5 mm, lessthan about 4 mm, less than about 3 mm, less than about 2 mm, less thanabout 1 mm, less than about 800 micrometers, less than 600 micrometers,less than 500 micrometers, less than 400 micrometers, less than about300 micrometers, less than about 200 micrometers, less than about 175micrometers, less than about 150 micrometers, less than about 125micrometers, less than about 100 micrometers, less than about 75micrometers, less than about 50 micrometers, etc. For example, in oneembodiment, the needle may have a rectangular cross section havingdimensions of 175 micrometers by 50 micrometers. In one set ofembodiments, the needle may have an aspect ratio of length to largestcross-sectional dimension of at least about 2:1, at least about 3:1, atleast about 4:1, at least 5:1, at least about 7:1, at least about 10:1,at least about 15:1, at least about 20:1, at least about 25:1, at leastabout 30:1. etc. In one embodiment, the needle is a microneedle. As anexample, microneedles such as those disclosed in U.S. Pat. No.6,334,856, issued Jan. 1, 2002, entitled “Microneedle Devices andMethods of Manufacture and Use Thereof,” by Allen, et al., may be usedto deliver and/or receive fluids or other materials to or from asubject. The microneedles may be hollow or solid, and may be formed fromany suitable material, e.g., metals, ceramics, semiconductors, organics,polymers, and/or composites. Examples include, but are not limited to,pharmaceutical grade stainless steel, titanium, nickel, iron, gold, tin,chromium, copper, alloys of these or other metals, silicon, silicondioxide, and polymers, including polymers of hydroxy acids such aslactic acid and glycolic acid polylactide, polyglycolide,polylactide-co-glycolide, and copolymers with polyethylene glycol,polyanhydrides, polyorthoesters, polyurethanes, polybutyric acid,polyvaleric acid, polylactide-co-caprotactone, polycarbonate,polymethacrylic acid, polyethylenevinyl acetate, polytetrafluorethylene,polymethyl methacrylate, polyacrylic acid, or polyesters.

In some cases, more than one microneedle may be used. For example,arrays of microneedles may be used, and the microneedles may be arrangedin the array in any suitable configuration, e.g., periodic, random, etc.In some cases, the array may have 2 or more, 3 or more, 4 or more, 5 ormore, 6 or more, 10 or more, 15 or more, 20 or more, 35 or more, 50 ormore, 100 or more, or any other suitable number of microneedles. In someembodiments, the device may have at least 3 but no more than 5 needlesor microneedles (or other skin insertion objects), at least 6 but nomore than 10 needles or microneedles, or at least 11 but no more than 20needles or microneedles. Typically, a microneedle will have an averagecross-sectional dimension (e.g., diameter) or less than about a micron.It should be understood that references to “needle” or “microneedle” asdiscussed herein are by way of example and ease of presentation only,and that in other embodiments, more than one needle and/or microneedlemay be present in any of the descriptions herein.

Those of ordinary skill in the art can arrange needles relative to theskin for these purposes including, in one embodiment, introducingneedles into the skin at an angle, relative to the skin's surface, otherthan 90°, i.e., to introduce a needle or needles into the skin in aslanting fashion so as to limit the depth of penetration. In anotherembodiment, however, the needles may enter the skin at approximately90°.

In some cases, the microneedles may be present in an array selected suchthat the density of microneedles within the array is between about 0.5needles/mm² and about 10 needles/mm², and in some cases, the density maybe between about 0.6 needles/mm2 and about 5 needles/mm², between about0.8 needles/mm² and about 3 needles/mm², between about 1 needles/mm² andabout 2.5 needles/mm², or the like. In some cases, the needles may bepositioned within the array such that no two needles are closer thanabout 1 mm, about 0.9 mm, about 0.8 mm, about 0.7 mm, about 0.6 mm,about 0.5 mm, about 0.4 mm, about 0.3 mm, about 0.2 mm, about 0.1 mm,about 0.05 mm, about 0.03 mm, about 0.01 mm, etc.

In another set of embodiments, the needles (or microneedles) may bechosen such that the area of the needles (determined by determining thearea of penetration or perforation on the surface of the skin of thesubject by the needles) allows for adequate flow of fluid to or from thesubject. The microneedles may be chosen to have smaller or larger areas(or smaller or large diameters), so long as the area of contact for themicroneedles to the skin is sufficient to allow adequate blood flow fromthe subject to the device. The needles or microneedles may have anysuitable cross-sectional area. For example, in certain embodiments, eachmicroneedle may be selected to have a cross-sectional area of at least 5nm², at least about 100 nm², at least about 500 nm², at least about atleast about 1,000 nm², at least about 3,000 nm², at least about 10,000nm², at least about 30,000 nm², at least about 100,000 nm², at leastabout 300,000 nm², at least about 1 microns², at least about 3 microns²,at least about 10 microns², at least about 30 microns², at least about100 microns², at least about 300 microns², at least about 500 microns²,at least about 1,000 microns², at least about 2,000 microns², at leastabout 2,500 microns², at least about 3,000 microns², at least about5,000 microns², at least about 8,000 microns², at least about 10,000microns², or at least about 25,000 microns². For example, in certainembodiments, the microneedles may be selected to have a combinedskin-penetration area of at least about 500 nm², at least about 1,000nm², at least about 3,000 nm², at least about 10, nm²nm2, at least about30,000 nm², at least about 100,000 nm², at least about 300,000 nm², atleast about 1 microns², at least about 3 microns², at least about 10microns², at least about 30 microns², at least about 100 microns², atleast about 300 microns², at least about 500 microns², at least about1,000 microns², at least about 2,000 microns², at least about 2,500microns, at least about 3,000 microns², at least about 5,000 microns²,at least about 8,000 microns², at least about 10,000 microns², at leastabout 35,000 microns², at least about 100,000 microns², etc., dependingon the application.

The needles or microneedles may have any suitable length, and the lengthmay be, in some cases, dependent on the application. For example,needles designed to only penetrate the epidermis may be shorter thanneedles designed to also penetrate the dermis, or to extend beneath thedermis or the skin. In certain embodiments, the needles or microneedlesmay have a maximum penetration into the skin, or insertion depth, of nomore than about 3 mm, no more than about 2 mm, no more than about 1.75mm, no more than about 1.5 mm, no more than about 1.25 mm, no more thanabout 1 mm, no more than about 900 microns, no more than about 800microns, no more than about 750 microns, no more than about 1500microns, no more than about 600 microns, no more than about 500 microns,no more than about 400 microns, no more than about 300 microns, no morethan about 200 microns, no more than about 175 micrometers, no more thanabout 150 micrometers, no more than about 125 micrometers, no more thanabout 100 micrometers, no more than about 75 micrometers, no more thanabout 50 micrometers, etc. In certain embodiments, the needles ormicroneedles may be selected so as to have a maximum insertion depth ofat least about 50 micrometers, at least about 100 micrometers, at leastabout 300 micrometers, at least about 500 micrometers, at least about 1mm, at least about 2 mm, at least about 3 mm, etc.

In one set of embodiments, the needles (or microneedles) may be coated.For example, the needles may be coated with a substance that isdelivered when the needles are inserted into the skin. For instance, thecoating may comprise heparin, an anticoagulant, an anti-inflammatorycompound, an analgesic, an anti-histamine compound or a vasodilator toassist with the flow of blood from the skin of the subject. The coatingmay comprise a drug or other therapeutic agent such as those describedherein. The drug or other therapeutic agent may be one used forlocalized delivery (e.g., of or proximate the region to which the coatedneedles or microneedles are applied), and/or the drug or othertherapeutic agent may be one intended for systemic delivery within thesubject.

At least some the skin insertion objects may be at least partiallycoated by a substance such as a drug, analgesic or agent by using dip orspray coating or other suitable technique. Thus, the substance may bedelivered to the skin by the substance dissolving or otherwise detachingfrom the substance transfer component at or in the skin or other subjectsite. Alternately, the substance may be delivered after a substancetransfer component penetrates the subject, e.g., in a way similar to ahypodermic needle. For example, a skin insertion object of the substancetransfer component may be inserted into the skin, and a substance may bepumped or pushed through a hole, groove or other channel of the skininsertion object (e.g., by a high pressure gas).

A drug may be any composition which possesses therapeutic, prophylactic,or diagnostic properties in vivo, for example when administered to ananimal, including mammals, such as humans. The drug can be for localtreatment or for regional or systemic therapy. The drug can be orinclude a peptide, protein, carbohydrate (including monosaccharides,oligosaccharides, and polysaccharides), nucleoprotein, mucoprotein,lipoprotein, glycoprotein, nucleic acid molecules (including any form ofDNA such as cDNA, RNA, or a fragment thereof, oligonucleotides, andgenes), nucleotide, nucleoside, lipid, biologically active organic orinorganic molecules, or combination thereof. Examples of suitabletherapeutic and/or prophylactic active agents include anti-infectives,analgesics, anti-inflammatories, steroids, decongestants, neuroactiveagents, anesthetics, and sedatives. Examples of suitable diagnosticagents include radioactive isotopes and radioopaque agents, metals,gases, labels including chromatographic, fluorescent, or enzymaticlabels.

Examples of biologically active polypeptides or proteins include, butare not limited to, glucagon, glucagon-like peptides such as, GLP-1,GLP-2 or other GLP analogs, derivatives or agonists of Glucagon LikePeptides, exendins such as, exendin-3 and exendin-4, derivatives,agonists and analogs thereof, vasoactive intestinal peptide (VIP),immunoglobulins, antibodies, cytokines (e.g., lymphokines, monokines,chemokines), interleukins, macrophage activating factors, interferons,erythropoietin, nucleases, tumor necrosis factor, colony stimulatingfactors (e.g., G-CSF), insulin, enzymes (e.g., superoxide dismutase,plasminogen activator, etc.), tumor suppressors, blood proteins,hormones and hormone analogs and agonists (e.g., follicle stimulatinghormone, growth hormone, adrenocorticotropic hormone, and luteinizinghormone releasing hormone (LHRH)), vaccines (e.g., tumoral, bacterialand viral antigens), antigens, blood coagulation factors, growth factors(NGF and EGF), gastrin, GRH, antibacterial peptides such as defensin,enkephalins, bradykinins, calcitonin and muteins, analogs, truncation,deletion and substitution variants and pharmaceutically acceptable saltsof all the foregoing. Suitable analgesics include but are not limited tolidocaine, bupivacaine, and tetracaine. Suitable steroids include butare not limited to cortisone, betametasone, budesonide and fluticasone.

In one set of embodiments, the needles or microneedles may be used todeliver a drug into the skin of a subject. The needles or microneedlesmay be at least partially coated, and the coating may comprise a drug orother therapeutic agent such as those described herein. For example, inone set of embodiments, at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, or substantially allof a needle or a microneedle may be coated, and one or more than oneneedle or microneedle may be coated in a device as discussed herein. Forinstance, at least about 25%, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 90%, orsubstantially all of the needles or microneedles in a device maycomprise a coating.

Without wishing to be bound by any theory, it is believed that, at leastin some cases, longer needles or microneedles may be useful for thedelivery of a drug or other therapeutic agent. For example, a needlehaving a greater depth of penetration into the skin may be useful fordelivering the drug or other therapeutic agent deeper into the skin,e.g., closer to capillaries within or below the skin, which may minimizethe distance the drug needs to travel before being availablesystemically and allow a more rapid onset of the drug effect. Inaddition, greater depth of penetration can be useful for deliveringgreater amounts of drug. A longer needle can have more surface areaexposed internally of the subject, relative to a shorter needle (e.g.,of the same diameter), and the increased surface area may allow more ofthe coating containing drug to be exposed internally of the skin. Thus,for example, a greater amount of drug may be delivered per needle ormicroneedle that enters the skin.

Accordingly, in certain embodiments, relatively long needles ormicroneedles may be used for the delivery of a drug or other therapeuticagent into the skin, for example. For instance, the average length ofthe needles or microneedles in the device may be at least about 200micrometers, at least about 300 micrometers, at least about 400micrometers, at least about 500 micrometers, at least about 600micrometers, at least about 750 micrometers, at least about 800micrometers, at least about 900 micrometers, at least about 1,000micrometers, at least about 1,200 micrometers, at least about 1,500micrometers, at least about 1,700 micrometers, or at least about 2,000micrometers in some embodiments.

Any of a variety of suitable techniques may be used to coat a needle ora microneedle. For instance, the needle or microneedle may be coated byexposing the needles or microneedles to a liquid containing a substanceto be coated thereon. For example, the needles or microneedles may bedipped into a liquid, a liquid may be sprayed on or aerosolized onto theneedles or microneedles, an electric field may be used to attract acharged liquid onto the needles or microneedles, etc.

In one embodiment, the fluid is delivered and/or received manually,e.g., by manipulating a plunger on a syringe. In another embodiment, thefluid can be delivered and/or received from the skin mechanically orautomatically, e.g., using a piston pump or the like. Fluid may also bereceived using vacuums such as those discussed herein. For example,vacuum may be applied to a conduit, such as a needle, in fluidiccommunication with a bodily fluid in order to draw up at least a portionof the fluid from the pooled region. In yet another embodiment, fluid isreceived using capillary action (e.g., using a microfluidic channel orhypodermic needle having a suitably narrow inner diameter). In stillanother embodiment, pressure may be applied to force fluid out of theneedle.

In some embodiments, a substance is delivered to a subject from adevice. In cases where the needle or other skin insertion object iscoated with a drug or other substance, the device may deliver the drugor substance to a subject by penetrating the skin with the coatedneedle. The substance may be delivered to or beneath the skin by thesubstance dissolving or otherwise detaching from the substance transfercomponent at the skin or other subject site. The device may or may notcause, fluid release from the subject. In some cases, fluid from thesubject is not received into the device and a vacuum source is notneeded. Also, in some cases, the device may additionally oralternatively deliver a fluid drug or other fluid substance to asubject. The fluid substance may delivered to or beneath the skinthrough hollow needles that transfer fluid from the device to thesubject.

As still another example, pressurized fluids may be used to deliverfluids or other materials into the skin, for instance, using a jetinjector or a “hypospray.” Typically, such devices produce ahigh-pressure “jet” of liquid or powder (e.g., a biocompatible liquid,such as saline) that drives material into the skin, and the depth ofpenetration may be controlled, for instance, by controlling the pressureof the jet. The pressure may come from any suitable source, e.g., astandard gas cylinder or a gas cartridge. A non-limiting example of sucha device can be seen in U.S. Pat. No. 4,103,684, issued Aug. 1, 1978,entitled “Hydraulically Powered Hypodermic Injector with Adapters forReducing and Increasing Fluid Injection Force,” by Ismach.

In some embodiments, fluid may be received using a hygroscopic agentapplied to the surface of the skin, or proximate the skin. For example,a device as described herein may contain a hygroscopic agent. In somecases, pressure may be applied to drive the hygroscopic agent into theskin. Hygroscopic agents typically are able to attract water from thesurrounding environment, for instance, through absorption or adsorption.Non-limiting examples of hygroscopic agents include sugar, honey,glycerol, ethanol, methanol, sulfuric acid, methamphetamine, iodine,many chloride and hydroxide salts, and a variety of other substances.Other examples include, but are not limited to, zinc chloride, calciumchloride, potassium hydroxide, or sodium hydroxide. In some cases, asuitable hygroscopic agent may be chosen based on its physical orreactive properties, e.g., inertness or biocompatibility towards theskin of the subject, depending on the application.

In some embodiments, the device may comprise a cutter able to cut orpierce the surface of the skin. The cutter may comprise any mechanismable to create a path through which fluids may be delivered and/orreceived from the skin. For example, the cutter may comprise ahypodermic needle, a blade (e.g., a knife blade, a serrated blade,etc.), a piercing element (e.g., a lancet or a solid or a hollowneedle), or the like, which can be applied to the skin to create asuitable conduit for the delivery and/or receiving of fluid from theskin. In one embodiment, a cutter is used to create such a pathway andremoved, then fluid may be delivered and/or received via this pathway.In another embodiment, the cutter remains in place within the skin, andfluid may be delivered and/or received through a conduit within thecutter.

In some embodiments, fluid may be received using an electric charge. Forexample, reverse iontophoresis may be used. Without wishing to be boundby any theory, reverse iontophoresis uses a small electric current todrive charged and highly polar compounds across the skin. Since the skinis negatively charged at physiologic pH, it acts as a permselectivemembrane to cations, and the passage of counterions across the skininduces an electroosmotic solvent flow that may carry neutral moleculesin the anode-to-cathode direction. Components in the solvent flow may beanalyzed as described elsewhere herein. In some instances, a reverseiontophoresis apparatus may comprise an anode cell and a cathode cell,each in contact with the skin. The anode cell may be filled, forexample, with an aqueous buffer solution (i.e., aqueous Tris buffer)having a pH greater than 4 and an electrolyte (i.e. sodium chloride).The cathode cell can be filled with aqueous buffer. As one example, afirst electrode (e.g., an anode) can be inserted into the anode cell anda second electrode (e.g., a cathode) can be inserted in the cathodecell. In some embodiments, the electrodes are not in direct contact withthe skin.

A current may be applied to induce reverse iontophoresis, therebyreceiving a fluid from the skin. The current applied may be, forexample, greater than 0.01 mA, greater than 0.3 mA, greater than 0.1 mA,greater than 0.3 mA, greater than 0.5 mA, or greater than 1 mA. Itshould be understood that currents outside these ranges may be used aswell. The current may be applied for a set period of time. For example,the current may be applied for greater than 30 seconds, greater than 1minute, greater than 5 minutes, greater than 30 minutes, greater than 1hour, greater than 2 hours, or greater than 5 hours. It should beunderstood that times outside these ranges may be used as well.

In one set of embodiments, the device may comprise a substance transfercomponent in the form of an apparatus for ablating the skin. Withoutwishing to be bound by any theory, it is believed that ablationcomprises removing a microscopic patch of stratum corneum (i.e.,ablation forms a micropore), thus allowing access to bodily fluids. Insome cases, thermal, radiofrequency, and/or laser energy may be used forablation. In some instances, thermal ablation may be applied using aheating element. Radiofrequency ablation may be carried out using afrequency and energy capable of heating water and/or tissue. A laser mayalso be used to irradiate a location on the skin to remove a portion. Insome embodiments, the beat may be applied in pulses such that a steeptemperature gradient exists essentially perpendicular to the surface ofthe skin. For example, a temperature of at least 100° C. at least 200°C., at least 300° C., or at least 400° C. may be applied for less than 1second, less than 0.1 seconds, less than 0.01 seconds, less than 0.005seconds, or less than 0.001 seconds.

In some embodiments, the device may comprise a substance transfercomponent in the form of a mechanism for taking a solid sample oftissue. For example, a solid tissue sample may be acquired by methodssuch as scraping the skin or cutting out a portion. Scraping maycomprise a reciprocating action whereby an instrument is scraped alongthe surface of the skin in two or more directions. Scraping can also beaccomplished by a rotating action, for example parallel to the surfaceof the skin and in one direction (i.e., with a roller drum) or parallelto the surface of the skin and in a circular manner (i.e., with adrilling instrument). A cutting mechanism may comprise a blade capableof making one or more incisions and a mechanism for removing a portionof tissue (i.e., by suction or mechanically picking up) or may use apincer mechanism for cutting out a portion of tissue. A cuttingmechanism may also function by a coring action. For example, a hollowcylindrical device can be penetrated into the skin such that acylindrical core of tissue may be removed. A solid sample may beanalyzed directly or may be liquefied prior to analysis. Liquefactioncan comprise treatment with organic solvents, enzymatic solutions,surfactants, etc.

The device may also contain, in some embodiments, a vacuum source. Insome cases, the vacuum source is one that is self-contained within thedevice, i.e., the device need not be connected to an external vacuumsource (e.g., a house vacuum) during use of the device to receive bloodfrom the skin. For example, in one set of embodiments, the vacuum sourcemay include a vacuum chamber having a pressure less than atmosphericpressure before blood (or other fluid) is received into the device,i.e., the vacuum chamber is at a “negative pressure” (that is, negativerelative to atmospheric pressure) or a “vacuum pressure” (or just havinga “vacuum”). For example, the vacuum in the vacuum chamber may be atleast about 50 mmHg, at least about 100 mmHg, at least about 150 mmHg,at least about 200 mmHg, at least about 250 mmHg, at least about 300mmHg, at least about 350 mmHg, at least about 400 mmHg, at least about450 mmHg, at least about 500 mmHg, at least 550 mmHg, at least 600 mmHg,at least 650 mmHg, at least about 700 mmHg, or at least about 750 mmHg,i.e., below atmospheric pressure. However, in other embodiments, itshould be understood that other pressures may be used and/or thatdifferent methods may be used to produce other pressures (greater thanor less than atmospheric pressure). As non-limiting examples, anexternal vacuum or a mechanical device may be used as the vacuum source;various additional examples are discussed in detail herein.

As a specific, non-limiting example, in one embodiment, a device may beused to receive fluid without an external power and/or a vacuum source.Examples of such devices include skin patches, strips, tapes, bandages,or the like. For instance, a skin patch may be contacted with the skinof a subject, and a vacuum created through a change in shape of aportion of the skin patch or other device (e.g., using a shape memorypolymer), which may be used to deliver and/or receive fluid from theskin. As a specific example, a shape memory polymer may be shaped to beflat at a first temperature (e.g., room temperature) but curved at asecond temperature (e.g., body temperature), and when applied to theskin, the shape memory polymer may alter from a flat shape to a curvedshape, thereby creating a vacuum. As another example, a mechanicaldevice may be used to create the vacuum. For example, springs, coils,expanding foam (e.g., from a compressed state), a shape memory polymer,shape memory metal, or the like may be stored in a compressed or woundreleased upon application to a subject, then released (e.g., unwinding,uncompressing, etc.), to mechanically create the vacuum. Thus, in somecases, the device is “pre-packaged” with a suitable vacuum source (e.g.,a pre-evacuated vacuum chamber); for instance, in one embodiment, thedevice may be applied to the skin and activated in some fashion tocreate and/or access the vacuum source. In yet another example, achemical reaction may be used to create a vacuum, e.g., a reaction inwhich a gas is produced, which can be harnessed to provide themechanical force to create a vacuum. In still another example, acomponent of the device may be able to create a vacuum in the absence ofmechanical force. In another example, the device may include aself-contained vacuum actuator, for example, chemical reactants, adeformable structure, a spring, a piston, etc.

In one set of embodiments, the device may be able to create a pressuredifferential (e.g. a vacuum). The pressure differential may be createdby a pressure regulator. As used here, “pressure regulator” is apressure controller component or system able to create a pressuredifferential between two or more locations. The pressure differentialshould be at least sufficient to urge the movement of fluid or othermaterial in accordance with various embodiments of the invention asdiscussed herein, and the absolute pressures at the two or morelocations are not important so long as their differential isappropriate, and their absolute values are reasonable for the purposesdiscussed herein. For example, the pressure regulator may produce apressure higher than atmospheric pressure in one location, relative to alower pressure at another location (atmospheric pressure or some otherpressure), where the differential between the pressures is sufficient tourge fluid in accordance with the invention. In another example, theregulator or controller will involve a pressure lower than atmosphericpressure (a vacuum) in one location, and a higher pressure al anotherlocation(s) (atmospheric pressure or a different pressure) where thedifferential between the pressures is sufficient to urge fluid inaccordance with the invention. Wherever “vacuum” or “pressure” is usedherein, in association with a pressure regulator or pressuredifferential of the invention, it should be understood that the oppositecan be implemented as well, as would be understood by those of ordinaryskill in the art, i.e., a vacuum chamber can be replaced in manyinstances with a pressure chamber, for creating a pressure differentialsuitable for urging the movement of fluid or other material.

The pressure regulator may be an external source of vacuum (e.g. a lab,clinic, hospital, etc., house vacuum line or external vacuum pump), amechanical device, a vacuum chamber, pre-packaged vacuum chamber, or thelike. In some cases, vacuum may be created manually, e.g., bymanipulating a syringe pump, a plunger, or the like, or the low pressuremay be created mechanically or automatically, e.g., using a piston pump,a syringe, a bulb, a Venturi tube, manual (mouth) suction, etc., or thelike. Vacuum chambers can be used in some embodiments, where the devicecontains, e.g., regions in which a vacuum exits or can be created (e.g.a variable volume chamber, a change in volume of which will affectvacuum or pressure). A vacuum chamber can include pre-evacuated (i.e.,pre-packaged) chambers or regions, and/or self-contained actuators. A“self-contained” vacuum (or pressure) regulator means one that isassociated with (e.g., on or within) the device, e.g. one that definesan integral part of the device, or is a separate component constructedand arranged to be specifically connectable to the particular device toform a pressure differential (i.e., not a connection to an externalsource of vacuum such as a hospital's, clinic's, or lab's house vacuumline, or a vacuum pump suitable for very general use). In someembodiments, the self-contained vacuum source may be actuated in somefashion to create a vacuum within the device. For instance, theself-contained vacuum source may include a piston, a syringe, amechanical device such as a vacuum pump able to create a vacuum withinthe device, and/or chemicals or other reactants that can react toincrease or decrease pressure which, with the assistance of mechanicalor other means driven by the reaction, can form a pressure differentialassociated with a pressure regulator. Chemical reaction can also drivemechanical actuation with or without a change in pressure based on thechemical reaction itself. A self-contained vacuum source can alsoinclude an expandable foam, a shape memory material, or the like.

One category of self-contained vacuum or pressure regulators of theinvention includes self-contained assisted regulators. These areregulators that, upon actuation (e.g., the push of a button, orautomatic actuation upon, e.g., removal from a package or urging adevice against the skin), a vacuum or pressure associated with thedevice is formed where the force that pressurizes or evacuates a chamberis not the same as the actuation force. Examples of self-containedassisted regulators include chambers evacuated by expansion driven by aspring triggered by actuation, release of a shape-memory material orexpandable material upon actuation, initiation of a chemical reactionupon actuation, or the like.

Another category of self-contained vacuum or pressure regulators of theinvention are devices that are not necessarily pre-packaged withpressure or vacuum, but which can be pressurized or evacuated, e.g. by asubject, health care professional at a hospital or clinic prior to use,e.g. by connecting a chamber of the device to a source of vacuum orpressure. For example, the subject, or another person, may actuate thedevice to create a pressure or vacuum within the device, for example,immediately prior to use of the device.

The vacuum or pressure regulator may be a “pre-packaged” pressure orvacuum chamber in the device when used (i.e., the device can be providedready for use by a subject or practitioner with an evacuated region onor in the device, without the need for any actuation to form the initialvacuum). A pre-packaged pressure or vacuum chamber regulator can, e.g.,be a region evacuated (relative to atmospheric pressure) uponmanufacture and/or at some point prior to the point at which it is usedby a subject or practitioner. For example, a chamber is evacuated uponmanufacture, or after manufacture but before delivery of the device tothe user, e.g. the clinician or subject. For instance, in someembodiments, the device contains a vacuum chamber having a vacuum of atleast about 50 mmHg, at least about 100 mmHg, at least about 150 mmHg,at least about 200 mmHg, at least about 250 mmHg, at least about 300mmHg, at least about 350 mmHg, at least about 400 mmHg, at least about450 mmHg, at least about 500 mmHg, at least about 550 mmHg, at leastabout 600 mmHg, at least about 650 mmHg, at least about 700 mmHg, or atleast about 750 mmHg below atmospheric pressure.

In one set of embodiments, a device of the present invention may nothave an external power and/or a vacuum source. In some cases, the deviceis “pre-loaded” with a suitable vacuum source; for instance, in oneembodiment, the device may be applied to the skin and activated in somefashion to create and/or access the vacuum source. As one example, adevice of the present invention may be contacted with the skin of asubject, and a vacuum created through a change in shape of a portion ofthe device (e.g., using a shape memory polymer), or the device maycontain one or more sealed, self-contained vacuum chambers, where a sealis punctured in some manner to create a vacuum. For instance, uponpuncturing the seal, a vacuum chamber may be in fluidic communicationwith a needle, which can be used to move the skin towards the device,receive fluid from the skin, or the like.

As another example, a shape, memory polymer may be shaped to be flat ata first temperature (e.g., room temperature) but curved at a secondtemperature (e.g., body temperature), and when applied to the skin, theshape memory polymer may alter from a flat shape to a curved shape,thereby creating a vacuum. As yet another example, a mechanical devicemay be used to create the vacuum. For example, springs, coils, expandingfoam (e.g., from a compressed state), a shape memory polymer, shapememory metal, or the like may be stored in a compressed or woundreleased upon application to a subject, then released (e.g., unwinding,uncompressing, etc.), to mechanically create the vacuum. Non-limitingexamples of shape-memory polymers and metals include Nitinol,compositions of oligo(epsilon-capiolactone)diol and crystallizableoligo(rho-dioxanone)diol, or compositions ofoligo(epsilon-caprolactone)dimethacrylate and n-butyl acrylate.

In yet another example, a chemical reaction may be used to create avacuum, e.g., a reaction in which a gas is produced, which can beharnessed to provide the mechanical force to create a vacuum. In someembodiments, the device may be used to create a vacuum automatically,once activated, without any external control by a user.

In one set of embodiments, the device contains a vacuum chamber that isalso used as a storage chamber to receive blood or other fluid receivedfrom the subject into the device. For instance, blood received from asubject through or via the substance transfer component may enter thevacuum chamber due to its negative pressure (i.e., because the chamberhas an internal pressure less than atmospheric pressure), and optionallystored in the vacuum chamber for later use. A non-limiting example isillustrated in FIG. 3. In this figure, device 600 contains vacuumchamber 610, which is connected to substance transfer component 620(which may include, e.g., one or more microneedles). Upon activation ofvacuum chamber 610 (e.g., using actuator 660, as discussed below),vacuum chamber 610 may be put into fluidic communication with substancetransfer component 620. Substance transfer component 620 may accordinglycause negative pressure to be applied to the skin of the subject, forinstance, due to the internal pressure within vacuum chamber 610. Fluid(e.g., blood) exiting the skin via substance transfer component 620 mayaccordingly be drawn into the device and into vacuum chamber 610, e.g.,through conduit 612. The fluid collected by the device can then beanalyzed within the device or removed from the device for analysis,storage, etc.

In another set of embodiments, however, the device may include separatevacuum chambers and storage chambers (e.g., chambers to store fluid suchas blood from the subject). The vacuum chamber and storage chambers maybe in fluid communication, and may have any suitable arrangement. Insome embodiments, the vacuum from the vacuum chamber may be used, atleast in part, to receive fluid from the skin, which is then directedinto a storage chamber, e.g., for later analysis or use, for example, asdiscussed below. As an example, blood may be received into the device,flowing towards a vacuum chamber, but the fluid may be prevented fromentering the vacuum chamber. For instance, in certain embodiments, amaterial permeable to gas but not to a liquid such as blood may be used.For example, the material may be a membrane such as a hydrophilic orhydrophobic membrane having a suitable porosity, a porous structure, aporous ceramic frit, a dissolvable interface (e.g., formed from a saltor a polymer, etc.), or the like.

One non-limiting example is illustrated in FIG. 4. In this figure,device 600 contains vacuum chamber 610 and storage chamber 615. Vacuumchamber 610 can be put in fluidic communication with storage chamber 615via conduit 612, which contains material 614. Material 614 may be anymaterial permeable to gas but not to a liquid in this example, e.g.material 614 may be a membrane such as a hydrophilic membrane or ahydrophobic membrane that has a porosity that allows gas exchange tooccur but does not allow the passage of blood from the subject. Whendevice 600 is actuated using actuator 660, blood (or other fluid) flowsthrough substance transfer component 620 via conduit 661 into collectionchamber 615 because of the internal vacuum pressure from vacuum chamber610, which is not completely impeded by material 614 since it ispermeable to gases. However, because of material 614, blood (or othersuitable bodily fluid) is prevented from entering vacuum chamber 610,and instead remains in storage chamber 615, e.g., for later analysis oruse.

In some embodiments, the flow of blood (or other fluid) into the storagechamber may be controlled using a flow controller. The flow controllermay be manually and/or automatically controlled to control the flow ofblood. The flow controller may activate or deactivate when a certainamount or volume of fluid has entered the storage chamber in certaincases. For instance, the flow controller may stop blood flow after apredetermined amount or volume of blood has entered the storage chamber,and/or the flow controller may be able to control the internal pressureof the storage chamber, e.g., to a specific level, such as apredetermined level. Examples of suitable flow controllers for thedevice include, but are not limited to, a membrane, a valve, adissolvable interface a gate, or the like.

One non-limiting example of a flow controller is now illustrated withreference to FIG. 5. In this example figure, device 600 includes avacuum chamber 610 and a storage chamber 615. Fluid entering device 600via substance transfer component 620 is prevented from entering storagechamber 615 due to flow controller 645 present within conduit 661.However, under suitable conditions, flow controller 645 may be opened,thereby allowing at least some fluid to enter storage chamber 615. Insome cases, for instance, storage chamber 615 also contains at least apartial vacuum, although this vacuum may be greater or less than thepressure within chamber 610. In other embodiments, flow controller 645may initially be open, or be externally controllable (e.g., via anactuator), or the like. In some cases, the flow controller may controlthe flow of fluid into the device such that, after collection, at leastsome vacuum is still present in the device.

Thus, in some cases, the device may be constructed and arranged toreproducibly obtain from the subject a controlled amount of fluid, e.g.,a controlled amount or volume of blood. The amount of fluid reproduciblyobtained from the subject may be controlled, for example, using flowcontrollers, materials permeable to gas but not to liquids, membranes,valves, pumps, gates, microfluidic systems, or the like, as discussedherein. In particular, it should be noted that the volume of blood orother fluid obtained from the subject need not be strictly a function ofthe initial vacuum pressure or volume within the device. For example, aflow controller may initially be opened (e.g., manually, automatically,electronically, etc.) to allow fluid to begin entering the device; andwhen a predetermined condition is reached (e.g., when a certain volumeor amount of blood has entered the device), the flow controller may beclosed at that point, even if some vacuum pressure remains within thedevice. In some cases, this control of fluid allows the amount of fluidreproducibly obtained from the subject to be controlled to a greatextent. For example, in one set of embodiments, the amount of fluidreceived from the subject may be controlled to be less than about 1 ml,may be less than about 300 microliters, less than about 100 microliters,less than about 30 microliters, less than about 10 microliters, lessthan about 3 microliters, less than about 1 microliter, etc.

Further examples of various embodiments of the invention are illustratedin FIGS. 6 and 8. In FIG. 7, device 500 is illustrated. In this example,device 500 includes a housing 501, an adhesive 502 for adhesion of thedevice to the skin, and a substance transfer component 503. In thisfigure, substance transfer component 503 includes a plurality ofmicroneedles 505, although other substance transfer components asdiscussed herein may also be used. Microneedles 505 are contained withinrecess 508. Also shown in FIG. 7 is vacuum chamber 513 which, in thisexample, is self-contained within device 500. Vacuum chamber 513 is influidic communication with recess 508 via channel 511, for example, ascontrolled by a controller or an actuator. Device actuator 560 is shownat the top of device 500. Device actuator 560 may be, for example, abutton, switch, slider, dial, etc. and may cause microneedles 505 tomove towards the skin when the device is placed on the skin. Forexample, the microneedles may be moved mechanically (e.g., compressionspring, Belleville spring, etc.), electrically (e.g., with the aid of aservo, which may be computer-controlled), pneumatically, etc. In somecases, device actuator 560 (or another actuator) may be used to causethe microneedles to be received from the skin, and/or the microneedlesmay be received automatically after delivering and/or receiving fluidfrom the subject, e.g., without any intervention by the subject, or byanother person. Non-limiting examples of such techniques are discussedin detail below.

Another example is illustrated with reference to FIG. 8. In this figure,device 500 includes a housing 501, an adhesive 502 for adhesion of thedevice to the skin, and a substance transfer component 503. In FIG. 8,substance transfer component 503 includes a plurality of microneedles505 within recess 508, although other substance transfer components asdiscussed herein may also be used. Device actuator 560 is shown at thetop of device 500. Device actuator 560 may be, for example, a button,switch, slider, dial, etc. and may cause microneedles 505 to movetowards the skin when the device is placed on the skin. For example, themicroneedles may be moved mechanically (e.g., compression spring,Belleville spring, etc.), electrically (e.g., with the aid of a servo,which may be computer-controlled), pneumatically, etc., e.g., viacomponent 584 (e.g., a piston, a screw, a mechanical linkage, etc.). Insome cases, device actuator 560 may also be able to receive themicroneedles from the skin after use, e.g., after a fluid is deliveredand/or received from the skin.

Chamber 513, in this figure, is a self-contained vacuum chamber. Vacuumchamber 513 is in fluidic communication with recess 508 via channel 511,for example, as controlled by a controller or an actuator. Alsoillustrated in FIG. 8 is fluid reservoir 540, which may contain a fluidsuch as an anticoagulant. The fluid may be introduced into blood orother fluid received from the skin. Controlling fluid flow from fluidreservoir may be one or more suitable fluidic control elements, e.g.,pumps, nozzles, valves, or the like, for example, pump 541 in FIG. 8.

In certain embodiments, the substance transfer component may be fastenedon a deployment actuator. In some cases, the deployment actuator canbring the substance transfer component to the skin, and in certaininstances, insert the substance transfer component into the skin. Forexample, the substance transfer component can be moved mechanically,electrically (e.g., with the aid of a servo, which may becomputer-controlled), pneumatically, via a piston, a screw, a mechanicallinkage, or the like. In one set of embodiments, the deployment actuatorcan insert the substance transfer component into the skin at a speed ofat least about 0.1 cm/s, at least about 0.3 cm/s, about 1 cm/s, at leastabout 3 cm/s, at least about 10 cm/s, at least about 30 cm/s, at leastabout 1 m/s, at least about 2 m/s, at least about 3 m/s, at least about4 m/s, at least about 5 m/s, at least about 6 m/s, at least about 7 m/s,at least about 8 m/s, at least about 9 m/s, at least about 10 m/s, atleast about 12 m/s, etc., at the point where the substance transfercomponent initially contacts the skin. Without wishing to be bound byany theory, it is believed that relatively faster insertion speeds mayincrease the ability of the substance transfer component to penetratethe skin (without deforming the skin or causing the skin to move inresponse), and/or decrease the amount of pain felt by the application ofthe substance transfer component to the skin. Any suitable method ofcontrolling the penetration speed into the skin may be used, includethose described herein.

As mentioned, in some embodiments, blood or other bodily fluids may bestored within the device for later use and/or analysis. For example, thedevice may be attached to a suitable external apparatus able to analyzea portion of the device (e.g., containing the fluid), and/or theexternal apparatus may remove at least some of the blood or other fluidfrom the device for subsequent analysis and/or storage. In some cases,however, at least some analysis may be performed by the device itself,e.g., using one or more sensors, etc., contained within the device.

For example, as discussed in detail below, in some cases, a storagechamber may contain a reagent or a reaction entity able to react with ananalyte suspected of being present in the blood (or other fluid)entering the device, and in some cases, the reaction entity may bedetermined to determine the analyte. In some cases, the determinationmay be made externally of the device, e.g., by determining a colorchange or a change in fluorescence, etc. The determination may be madeby a person, or by an external apparatus able to analyze at least aportion of the device. In some cases, the determination may be madewithout removing blood from the device, e.g., from the storage chamber.(In other cases, however, blood or other fluid may first be removed fromthe device before being analyzed.) For example, the device may includeone or more sensors (e.g., ion sensors such as K+ sensors, colorimetricsensors, fluorescence sensors, etc.), and/or contain “windows” thatallow light to penetrate the device. The windows may be formed of glass,plastic, etc., and may be selected to be at least partially transparentto one or a range of suitable wavelengths, depending on the analyte orcondition to be determined. As a specific example, the entire device (ora portion thereof) may be mounted in an external apparatus, and lightfrom the external apparatus may pass through or otherwise interact withat least a portion of the device (e.g., be reflected or refracted viathe device) to determine the analyte and/or the reaction entity.

In one aspect, the device may be interfaced with an external apparatusable to determine an analyte contained within a fluid in the device, forexample within a storage chamber as discussed herein. For example, thedevice may be mounted on an external holder, the device may include aport for transporting fluid out of the device, the device may include awindow for interrogating a fluid contained within the device, or thelike. Examples may be seen in U.S. patent application Ser. No.13/006,165 filed on Jan. 13, 2011, entitled “Sampling DeviceInterfaces.” incorporated herein by reference in its entirety.

Thus, the device, in certain embodiments, may contain a portion able todetermine a fluid received from the skin. For example, a portion of thedevice may contain a sensor, or reagents able to interact with ananalyte contained or suspected to be present within the received fluidfrom the subject, for example, a marker for a disease state. The sensormay be embedded within or integrally connected to the device, orpositioned remotely but with physical, electrical, and/or opticalconnection with the device so as to be able to sense a chamber within orfluid from the device. For example, the sensor may be in fluidiccommunication with fluid received from a subject, directly, via amicrofluidic channel, an analytical chamber, etc. The sensor may be ableto sense an analyte, e.g., one that is suspected of being in a fluidreceived from a subject. For example, a sensor may be free of anyphysical connection with the device, but may be portioned so as todetect the results of interaction of electromagnetic radiation, such asinfrared, ultraviolet, or visible light, which has been directed towarda portion of the device, e.g., a chamber within the device. As anotherexample, a sensor may be positioned on or within the device, and maysense activity in a chamber by being connected optically to the chamber.Sensing communication can also be provided where the chamber is incommunication with a sensor fluidly, optically or visually, thermally,pneumatically, electronically, or the like, so as to be able to sense acondition of the chamber. As one example, the sensor may be positioneddownstream of a chamber, within a channel such a microfluidic channel,on an external apparatus, or the like. Thus, the invention provides, incertain embodiments, sensors able to determine an analyte. Suchdetermination may occur within the skin, and/or externally of thesubject, e.g., within a device on the surface of the skin, depending onthe embodiment.

“Determine,” in this context, generally refers to the analysis of aspecies, for example, quantitatively or qualitatively, and/or thedetection of the presence or absence of the species. “Determining” mayalso refer to the analysis of an interaction between two or morespecies, for example, quantitatively or qualitatively, and/or bydetecting the presence or absence of the interaction, e.g. determinationof the binding between two species. The species may be, for example, abodily fluid and/or an analyte suspected of being present in the bodilyfluid. “Determining” also means detecting or quantifying interactionbetween species.

Non-limiting examples of sensors include dye-based detection systems,affinity-based detection systems, microfabricated gravimetric analyzers,CCD cameras, optical detectors, optical microscopy systems, electricalsystems, thermocouples and thermistors, pressure sensors, etc. Those ofordinary skill in the art will be able to identify other suitablesensors. The sensor can include a colorimetric detection system in somecases, which may be external to the device, or microfabricated into thedevice in certain cases. As an example of a colorimetric detectionsystem, if a dye or a fluorescent entity is used (e.g. in a particle),the colorimetric detection system may be able to detect a change orshift in the frequency and/or intensity of the dye or fluorescententity.

Examples of sensors include, but are not limited to, pH sensors, opticalsensors, ion sensors, colorimetric sensors, a sensor able to detect theconcentration of a substance, or the like, e.g., as discussed herein.For instance, in one set of embodiments, the device may include an ionselective electrode. The ion selective electrode may be able todetermine a specific ion and/or ions such as K+, H+, Na+, Ag+, Pb2+,Cd2+, or the like. Various ion selective electrodes can be obtainedcommercially. As a non-limiting example, a potassium-selective electrodemay include an ion exchange resin membrane, using valinomycin, apotassium channel, as the ion carrier in the membrane to providepotassium specificity.

Examples of analytes that the sensor may be used to determine include,but are not limited to, pH or metal ions, proteins, nucleic acids (e.g.DNA, RNA, etc.), drugs, sugars (e.g., glucose), hormones (e.g.,estradiol, estrone, progesterone, progestin, testosterone,androstenedione, etc.), carbohydrates, or other analytes of interest.Other conditions that can be determined can include pH changes, whichmay indicate disease, yeast infection, periodontal disease at a mucosalsurface, oxygen or carbon monoxide levels which indicate lungdysfunction, and drug levels, e.g., legal prescription levels of drugssuch as coumadin, other drugs such as nicotine, or illegal such ascocaine. Further examples of analytes include those indicative ofdisease, such as cancer specific markers such as CEA and PSA, viral andbacterial antigens, and autoimmune indicators such as antibodies todouble stranded DNA, indicative of Lupus. Still other conditions includeexposure to elevated carbon monoxide, which could be from an externalsource or due to sleep apnea, too much heat (important in the case ofbabies whose internal temperature controls are not fullyself-regulating) or from fever. Still other potentially suitableanalytes include various pathogens such as bacteria or viruses, and/ormarkers produced by such pathogens.

As additional non-limiting examples, the sensor may contain an antibodyable to interact with a marker for a disease state, an enzyme such asglucose oxidase or glucose 1-dehydrogenase able to detect glucose, orthe like. The analyte may be determined quantitatively or qualitatively,and/or the presence or absence of the analyte within the received fluidmay be determined in some cases. Those of ordinary skill in the art willbe aware of many suitable commercially-available sensors, and thespecific sensor used may depend on the particular analyte being sensed.For instance, various non-limiting examples of sensor techniques includepressure or temperature measurements, spectroscopy such as infrared,absorption, fluorescence, UV/visible, FTIR (“Fourier Transform InfraredSpectroscopy”), or Raman; piezoelectric measurements; immunoassays;electrical measurements, electrochemical measurements (e.g.,ion-specific electrodes); magnetic measurements, optical measurementssuch as optical density measurements; circular dichroism; lightscattering measurements such as quasielectric light scattering;polarimetry; refractometry; chemical indicators such as dyes; orturbidity measurements, including nephelometry.

In one set of embodiments, a sensor in the device may be used todetermine a condition of the blood present within the device. Forexample, the sensor may indicate the condition of analytes commonlyfound within the blood, for example, O2, K+, hemoglobin, Na+, glucose,or the like. As a specific non-limiting example, in some embodiments,the sensor may determine the degree of hemolysis within blood containedwithin the device. Without wishing to be bound by any theory, it isbelieved that in some cases, hemolysis of red blood cells may cause therelease of potassium ions and/or free hemoglobin into the blood. Bydetermining the levels of potassium ions, and/or hemoglobin (e.g., bysubjecting the device and/or the blood to separate cells from plasma,then determining hemoglobin in the plasma using a suitable colorimetricassay), the amount of blood lysis or “stress” experienced by the bloodcontained within the device may be determined. Accordingly, in one setof embodiments, the device may indicate the usability of the blood (orother fluid) contained within the device, e.g., by indicating the degreeof stress or the amount of blood lysis. Other examples of devicessuitable for indicating the usability of the blood (or other fluid)contained within the device are also discussed herein (e.g., byindicating the amount of time blood has been contained in the device,the temperature history of the device, etc.).

For instance, fluids received from the subject will often containvarious analytes within the body that are important for diagnosticpurposes, for example, markers for various disease states, such asglucose (e.g., for diabetics); other example analytes include ions suchas sodium, potassium, chloride, calcium, magnesium, and/or bicarbonate(e.g., to determine dehydration); gases such as carbon dioxide oroxygen; H+ (i.e., pH); metabolites such as urea, blood urea nitrogen orcreatinine; hormones such as estradiol, estrone, progesterone,progestin, testosterone, androstenedione, etc. (e.g., to determinepregnancy, illicit drug use, or the like): or cholesterol. Otherexamples include insulin, or hormone levels. As discussed herein,certain embodiments of the present invention are generally directed atmethods for receiving fluids from the body, and optionally determiningone or more analytes within the received fluid. Thus, in someembodiments, at least a portion of the fluid may be stored, and/oranalyzed to determine one or more analytes, e.g., a marker for a diseasestate, or the like. The fluid received from the skin may be subjected tosuch uses, and/or one or more materials previously delivered to the skinmay be subject to such uses.

Still other potentially suitable analytes include various pathogens suchas bacteria or viruses, and/or markers produced by such pathogens. Thus,in certain embodiments of the invention, as discussed below, one or moreanalytes within the pooled region of fluid may be determined in somefashion, which may be useful in determining a past, present and/orfuture condition of the subject.

In some embodiments, the device may connected to an external apparatusfor determining at least a portion of the device, a fluid removed fromthe device, an analyte suspected of being present within the fluid, orthe like. For example, the device may be connected to an externalanalytical apparatus, and fluid removed from the device for lateranalysis, or the fluid may be analyzed within the device in situ, e.g.,by adding one or more reaction entities to the device, for instance, toa storage chamber, or to analytical chamber within the device. Forexample, in one embodiment, the external apparatus may have a port orother suitable surface for mating with a port or other suitable surfaceon the device, and blood or other fluid can be removed from the deviceusing any suitable technique, e.g., using vacuum or pressure, etc. Theblood may be removed by the external apparatus, and optionally, storedand/or analyzed in some fashion. For example, in one set of embodiments,the device may include an exit port for removing a fluid from the device(e.g., blood). In some embodiments, fluid contained within a storagechamber in the device may be removed from the device, and stored forlater use or analyzed outside of the device. In some cases, the exitport may be separate from the substance transfer component. An exampleis shown with exit port 670 and substance transfer component 620 indevice 600 in FIG. 6. As shown in this figure, the exit port can be influidic communication with vacuum chamber 610, which can also serve as afluid reservoir in some cases.

In one set of embodiments, the device may include an anticoagulant or astabilizing agent for stabilizing the fluid received from the skin. Forexample, the fluid may be stored within the device for a certain periodof time, and/or the device (or a portion thereof) may be moved orshipped to another location for analysis or later use. For instance, adevice may contain anticoagulant or a stabilizing agent in a storagechamber. In some cases, more than one anticoagulant may be used, e.g.,in the same storage chamber, or in more than one storage chamber.

As a specific-non-limiting example, an anticoagulant may be used forblood received from the skin. Examples of anticoagulants include, butare not limited to, heparin, citrate, thrombin, oxalate,ethylenediaminetetraacetic acid (EDTA), sodium polyanethol sulfonate,acid citrate dextrose. Other agents may be used in conjunction orinstead of anticoagulants, for example, stabilizing agents such assolvents, diluents, buffers, chelating agents, antioxidants, bindingagents, preservatives, antimicrobials, or the like. Examples ofpreservatives include, for example, benzalkonium chloride,chlorobutanol, parabens, or thimerosal. Non-limiting examples ofantioxidants include ascorbic acid, glutathione, lipoic acid, uric acid,carotenes, alpha-tocopherol, ubiquinol, or enzymes such as catalase,superoxide dismutase, or peroxidases. Examples of microbials include,but are not limited to, ethanol or isopropyl alcohol, azides, or thelike. Examples of chelating agents include, but are not limited to,ethylene glycol tetraacetic acid or ethylenediaminetetraacetic acid.Examples of buffers include phosphate buffers such as those known toordinary skill in the art.

In one set of embodiments, at least a portion of the device may becolored to indicate the anticoagulant(s) contained within the device. Insome cases, the colors used may be identical or equivalent to thatcommercially used for Vacutainers™, Vacuettes™, or othercommercially-available phlebotomy equipment. For example, lavenderand/or purple may indicate ethylenediaminetetraacetic acid, light bluemay indicate citrate, dark blue may indicate ethylenediaminetetraaceticacid, green may indicate heparin, gray may indicate a fluoride and/or anoxalate, orange may indicate a thrombin, yellow may indicate sodiumpolyanethol sulfonate and/or acid citrate dextrose, black may indicatecitrate, brown may indicate heparin, etc. In other embodiments, however,other coloring systems may be used.

Other coloring systems may be used in other embodiments of theinvention, not necessarily indicative of anticoagulants. For example, inone set of embodiments, the device carries a color indicative of arecommended bodily use site for the device, e.g., a first colorindicative of a device suitable for placement on the back, a secondcolor indicative of a device suitable for placement on a leg, a thirdcolor indicative of a device suitable for placement on the arm, etc.

As mentioned, in one set of embodiments, a device of the invention asdiscussed herein may be shipped to another location for analysis. Insome cases, the device may include an anticoagulant or a stabilizingagent contained within the device, e.g., within a storage chamber forthe fluid. Thus, for example, fluid such as blood received from the skinmay be delivered to a chamber (e.g., a storage chamber) within thedevice, then the device, or a portion of the device (e.g., a module) maybe shipped to another location for analysis. Any form of shipping may beused, e.g., via mail.

Non-limiting examples of various devices of the invention are shown inFIG. 1. In FIG. 1A, device 90 is used for receiving a fluid from asubject when the device is placed on the skin of a subject. Device 90includes sensor 95 and substance transfer component 92, e.g., includinga needle, a microneedle, etc., as discussed herein. In fluidiccommunication with substance transfer component 92 via fluidic channel99 is sensing chamber 97. In one embodiment, sensing chamber 97 maycontain agents such as particles, enzymes, dyes, etc., for analyzingbodily fluids, such as interstitial fluid or blood. In some cases, fluidmay be received using substance transfer component 92 by a vacuum, forexample, a self-contained vacuum contained within device 90. Optionally,device 90 also contains a display 94 and associated electronics 93,batteries or other power supplies, etc., which may be used to displaysensor readings obtained via sensor 95. In addition, device 90 may alsooptionally contain memory 98, transmitters for transmitting a signalindicative of sensor 95 to a receiver, etc.

In the example shown in FIG. 1A, device 90 may contain a vacuum source(not shown) that is self-contained within device 90, although in otherembodiments, the vacuum source may be external to device 90. (In stillother instances, other systems may be used to deliver and/or receivefluid from the skin, as is discussed herein.) In one embodiment, afterbeing placed on the skin of a subject, the skin may be drawn upward intoa recess of the substance transfer component 92, for example, uponexposure to the vacuum source. Access to the vacuum source may becontrolled by any suitable method, e.g., by piercing a seal or a septum;by opening a valve or moving a gate, etc. For instance, upon activationof device 90, e.g., by the subject, remotely, automatically, etc., thevacuum source may be put into fluidic communication with the recess suchthat skin is drawn into the recess due to the vacuum. Skin drawn intothe recess may come into contact with a skin insertion object (e.g.,solid or hollow needles), which may, in some cases, pierce the skin andallow a fluid to be delivered and/or received from the skin. In anotherembodiment, a skin insertion object may be actuated and moved downwardto come into contact with the skin, and optionally retracted after use.

Another non-limiting example of a device is shown in FIG. 1B. Thisfigure illustrates a device useful for delivering a fluid to thesubject. Device 90 in this figure includes substance transfer component92, e.g., including a needle, a microneedle, etc., as discussed herein.In fluidic communication with substance transfer component 92 viafluidic channel 99 is chamber 97, which may contain a drug or otheragent to be delivered to the subject. In some cases, fluid may bedelivered with a pressure controller, and/or received using substancetransfer component 92 by a vacuum, for example, a self-contained vacuumcontained within device 90. For instance, upon creating a vacuum, skinmay be drawn up towards substance transfer component 92, and thesubstance transfer component 92 may pierce the skin. Fluid from chamber97 can then be delivered into the skin through fluid channel 99 andsubstance, transfer component 92. Optionally, device 90 also contains adisplay 94 and associated electronics 93, batteries or other powersupplies, etc., which may be used control delivery of fluid to the skin.In addition, device 90 may also optionally contain memory 98,transmitters for transmitting a signal indicative of device 90 or fluiddelivery to a receiver, etc.

Yet another non-limiting example of a device of the invention is shownin FIG. 2. FIG. 2A illustrates a view of the device (with the coverremoved), while FIG. 2B schematically illustrates the device incross-section. In FIG. 2B, device 50 includes a needle 52 containedwithin a recess 55. Needle 52 may be solid or hollow, depending on theembodiment. Device 50 also includes a self-contained vacuum chamber 60,which wraps around the central portion of the device where needle 52 andrecess 55 are located. A channel 62 connects vacuum chamber 60 withrecess 55, separated by a foil or a membrane 67. Also shown in device 50is button 58. When pushed, button 58 breaks foil 67, thereby connectingvacuum chamber 50 with recess 55, creating a vacuum in recess 55. Thevacuum may be used, for example, to draw skin into recess 55, preferablysuch that it contacts needle 52 and pierces the surface, thereby gainingaccess to an internal fluid. The fluid may be controlled, for example,by controlling the size of needle 52, und thereby the depth ofpenetration. For example, the penetration may be limited to theepidermis, e.g., to collect interstitial fluid, or to the dermis, e.g.,to collect blood. In some cases, the vacuum may also be used to at leastpartially secure, device 50 on the surface of the skin, and/or to assistin the receiving of fluid from the skin. For instance, fluid may flowinto channel 62 under action of the vacuum, and optionally to sensor 61,e.g., for detection of an analyte contained within the fluid. Forinstance, sensor 61 may produce a color change if an analyte is present,or otherwise produce a detectable signal.

Other components may be added to the example of the device illustratedin FIG. 2, in some embodiments of the invention. For example, device 50may contain a cover, displays, ports, transmitters, sensors, channelssuch as microfluidic channels, chambers, and/or various electronics,e.g., to control or monitor fluid transport into or out of device 50, todetermine an analyte present within a fluid delivered and/or receivedfrom the skin, to determine the status of the device, to report ortransmit information regarding the device and/or analytes, or the like,as is discussed in more detail herein. As another example, device 50 maycontain an adhesive, e.g., on surface 54, for adhesion of the device tothe skin.

Yet another non-limiting example is illustrated with reference to FIG.2C. In this example, device 500 includes a housing 501, and anassociated substance transfer component 503. Substance transfercomponent 503 includes a plurality of needles or microneedles 505,although other skin insertion objects or flow activators as discussedherein may also be used. Also shown in FIG. 5 is sensor 510, connectedvia channels 511 to recess 508 containing needles or microneedles 505.Chamber 513 may be a self-contained vacuum chamber, and chamber 513 maybe in fluidic communication with recess 508 via channel 511, forexample, as controlled by a controller or an actuator (not shown). Inthis figure, device 500 also contains display 525, which is connected tosensor 510 via electrical connection 522. As an example of use of device500, when fluid is drawn from the skin (e.g., blood, interstitial fluid,etc.), the fluid may flow through channel 511 to be determined by sensor510, e.g., due to action of the vacuum from vacuum chamber 513. In somecases, the vacuum is used, for example, to draw skin into recess 508,preferably such that it contacts needles or microneedles 505 and piercesthe surface of the skin to gain access to a fluid internal of thesubject, such as blood or interstitial fluid, etc. The fluid may becontrolled, for example, by controlling the size of needle 505, andthereby the depth of penetration. For example, the penetration may belimited to the epidermis, e.g., to collect interstitial fluid, or to thedermis, e.g., to collect blood. Upon determination of the fluid and/oran analyte present or suspected to be present within the fluid, amicroprocessor or other controller may display on display 525 a suitablesignal. As is discussed below, a display is shown in this figure by wayof example only; in other embodiments, no display may be present, orother signals may be used, for example, lights, smell, sound, feel,taste, or the like.

In some cases, more than one substance transfer component may be presentwithin the device. For instance, the device may be able to be usedrepeatedly, and/or the device may be able to deliver and/or receivefluid at more than one location on a subject, e.g., sequentially and/orsimultaneously. In some cases, the device may be able to simultaneouslydeliver and receive fluid to and from a subject. A non-limiting exampleof a device having more than one substance transfer component isillustrated with reference to FIG. 2B. In this example, device 500contains a plurality of structures such as those described herein fordelivering and/or receiving fluid from a subject. For example, device500 in this example contains 3 such units, although any number of unitsare possible in other embodiments. In this example, device 500 containsthree such substance transfer components 575. Each of these substancetransfer components may independently have the same or differentstructures, depending on the particular application, and they may havestructures such as those described herein. In some embodiments, thedevice may be an electrical and/or a mechanical device applicable oraffixable to the surface of the skin, e.g., using adhesive, or othertechniques such as those described herein. The adhesive may be permanentor temporary, and may be used to affix the device to the surface of theskin. The adhesive may be any suitable adhesive, for example, a pressuresensitive adhesive, a contact adhesive, a permanent adhesive, ahydrogel, a cyanoacrylate, a glue, a gum, hot melts, an epoxy, or thelike. In some cases, the adhesive is chosen to be biocompatible orhypoallergenic.

In another set of embodiments, the device may be mechanically held tothe skin, for example, the device may include mechanical elements suchas straps, belts, buckles, strings, ties, elastic bands, or the like.For example, a strap may be worn around the device to hold the device inplace against the skin of the subject. In yet another set ofembodiments, a combination of these and/or other techniques may be used.As one non-limiting example, the device may be affixed to a subject'sarm or leg using adhesive and a strap.

As another example, the device may be a handheld device that is appliedto the surface of the skin of a subject. In some cases, however, thedevice may be sufficiently small or portable that the subject canself-administer the device. In certain embodiments, the device may alsobe powered. In some instances, the device may be applied to the surfaceof the skin, and is not inserted into the skin. In other embodiments,however, at least a portion of the device may be inserted into the skin,for example, mechanically. For example, in one embodiment, the devicemay include a cutter, such as a hypodermic needle, a knife blade, apiercing element (e.g., a solid or hollow needle), or the like, asdiscussed herein.

Any or all of the arrangements described herein can be providedproximate a subject, for example on or proximate a subject's skin.Activation of the devices can be carried out in a variety of ways. Inone embodiment, a device can be applied to a subject and a region of thedevice activated (e.g., pushed, pressed, or tapped by a user) to injecta needle or a microneedle so as to access interstitial fluid. The sameor a different tapping or pushing action can activate a vacuum source,open and/or close one or more of a variety of valves, or the like. Thedevice can be a simple one in which it is applied to the skin andoperates automatically (where e.g., application to the skin accessesinterstitial fluid and draws interstitial fluid into an analysis region)or the device can be applied to the skin and one tapping or otheractivation can cause fluid to flow through administration of a needle ora microneedle, opening of a valve, activation of vacuum, or anycombination. Any number of activation protocols can be carried out by auser repeatedly pushing or tapping a location or selectively,sequentially, and/or periodically activating a variety of switches. Inanother arrangement, activation of needles or microneedles, creation ofsuction blisters, opening and/or closing of valves, and other techniquesto facilitate one or more analysis can be carried out electronically orin other manners facilitated by the subject or by an outside controllingentity. For example, a device or patch can be provided proximate asubject's skin and a radio frequency, electromagnetic, or other signalcan be provided by a nearby controller or a distant source to activateany of the needles, blister devices, valves or other components of thedevices described so that any assay or assays can be carried out asdesired.

In some embodiments, fluid may be delivered to the subject, and suchfluids may contain materials useful for delivery, e.g., forming at leasta portion of the fluid, dissolved within the fluid, carried by the fluid(e.g., suspended or dispersed), or the like. Examples of suitablematerials include, but are not limited to, particles such asmicroparticles or nanoparticles, a chemical, a drug or a therapeuticagent, a diagnostic agent, a carrier, or the like.

As used herein, the term “fluid” generally refers to a substance thattends to flow and to conform to the outline of its container. Typically,fluids are materials that are unable to withstand a static shear stress,and when a shear stress is applied, the fluid experiences a continuingand permanent distortion. The fluid may have any suitable viscosity thatpermits at least some flow of the fluid. Non-limiting examples of fluidsinclude liquids and gases, but may also include free-flowing solidparticles, viscoelastic fluids, and the like. For example, the fluid mayinclude a flowable matrix or a gel, e.g., formed from biodegradableand/or biocompatible material such as polylactic acid, polyglycolicacid, poly(lactic-co-glycolic acid), etc., or other similar materials.

In some cases, fluids or other materials delivered to the subject may beused for indication of a past, present and/or future condition of thesubject. Thus, the condition of the subject to be determined may be onethat is currently existing in the subject, and/or one that is notcurrently existing, but the subject is susceptible or otherwise is at anincreased risk to that condition. The condition may be a medicalcondition, e.g., diabetes or cancer, or other physiological conditions,such as dehydration, pregnancy, illicit drug use, or the like. In oneset of embodiments, the materials may include a diagnostic agent, forexample, one which can determine an analyte within the subject, e.g.,one that is a marker for a disease state. As a specific non-limitingexample, material delivered to the skin, e.g., to the dermis orepidermis, to a pooled region of fluid, etc., of a subject may include aparticle including an antibody directed at a marker produced bybacteria. In other cases, however, the materials delivered to thesubject may be used to determine conditions that are external to thesubject. For example, the materials may contain reaction entities ableto recognize pathogens or other environmental conditions surrounding thesubject, for example, an antibody able to recognize, an externalpathogen (or pathogen marker). As a specific example, the pathogen maybe anthrax and the antibody may be an antibody to anthrax spores. Asanother example, the pathogen may be a Plasmodia (some species of whichcauses malaria) and the antibody may be an antibody that recognizes thePlasmodia.

According to one aspect of the invention, the device is of a relativelysmall size. In some embodiments, the device may be sized such that it iswearable and/or carryable by a subject. For example, the device may beself-contained, needing no wires, cables, tubes, external structuralelements, or other external support. The device may be positioned on anysuitable position of the subject, for example, on the arm or leg, on theback, on the abdomen, etc. As mentioned, in some embodiments, the devicemay be affixed or held onto the surface of the skin using any suitabletechnique, e.g., using adhesives, mechanical elements such as straps,bells, buckles, strings, ties, elastic bands, or the like. In somecases, the device may be positioned on the subject such that the subjectis able to move around (e.g., walking, exercising, typing, writing,drinking or eating, using the bathroom, etc.) while wearing the device.For example, the device may have a mass and/or dimensions such that thesubject is able to wear the device for at least about 5 minutes, and insome cases for longer periods of time, e.g., at least about 10 minutes,at least about 15 minutes, at least about 30 minutes, at least about 45minutes, at least about 1 hour, at least about 3 hours, at least 5hours, at least about 8 hours, at least about 1 day, at least about 2days, at least about 4 days, at least about 1 week, at least about 2weeks, at least about 4 weeks, etc.

In some embodiments, the device is relatively lightweight. For example,the device may have a mass of no more than about 1 kg, no more thanabout 300 g, no more than about 150 g, no more than about 100 g, no morethan about 50 g, no more than about 30 g, no more than about 25 g, nomore than about 20 g, no more than about 10 g, no more than about 5 g,or no more than about 2 g. For instance, in various embodiments, thedevice has a mass of between about 2 g and about 25 g, a mass of betweenabout 2 g and about 10 g, a mass of between 10 g and about 50 g, a massof between about 30 g and about 150 g, etc.

The device, in some cases, may be relatively small. For example, thedevice may be constructed and arranged to lie relatively close to theskin. Thus, for instance, the device may have a largest verticaldimension, extending from the skin of the subject when the device ispositioned on the skin, of no more than about 25 cm, no more than about10 cm, no more than about 7 cm, no more than about 5 cm, no more thanabout 3 cm, no more than about 2 cm, no more than about 1 cm, no morethan about 8 mm, no more than about 5 mm, no more than about 3 mm, nomore than about 2 mm, no more than about 1 mm, or no more than about 0.5mm. In some cases, the device may have a largest vertical dimension ofbetween about 0.5 cm and about 1 cm, between about 2 and about 3 cm,between about 2.5 cm and about 5 cm, between about 2 cm and about 7 cm,between about 0.5 mm and about 7 cm, etc.

In another set of embodiments, the device may have a relatively smallsize. For example, the device may have a largest lateral dimension(e.g., parallel to the skin) of no more than about 25 cm, no more thanabout 10 cm, no more than about 7 cm, no more than about 5 cm, no morethan about 3 cm, no more than about 2 cm, or no more than about 1 cm. Insome cases, the device may have a largest lateral dimension of betweenabout 0.5 cm and about 1 cm, between about 2 and about 3 cm, betweenabout 2.5 cm and about 5 cm, between about 2 cm and about 7 cm, etc.

Combinations of these and/or other dimensions are also possible in otherembodiments. As non-limiting examples, the device may have a largestlateral dimension of no more than about 5 cm, a largest verticaldimension of no more than about 1 cm, and a mass of no more than about25 g; or the device may have a largest lateral dimension of no more thanabout 5 cm, a largest vertical dimension of no more than about 1 cm, anda mass of no more than about 25 g; etc.

In certain embodiments, the may also include a device actuator. Thedevice actuator may be constructed and arranged to cause exposure of thesubstance transfer component to the skin upon actuation of the deviceactuator. For example, the activator may cause the substance transfercomponent to release a chemical to contact the skin, a microneedle orother substance transfer component to be driven into the skin, a vacuumto be applied to the skin, a jet of fluid to be directed to the skin, orthe like. The device actuator may be actuated by the subject, and/or byanother person (e.g., a health care provider), or the device itself maybe self-actuating, e.g., upon application to the skin of a subject. Theactuator may be actuated once, or multiple times in some cases.

The device may be actuated, for example, by pushing a button, pressing aswitch, moving a slider, turning a dial, or the like. The subject,and/or another person, may actuate the actuator. In some cases, thedevice may be remotely actuated. For example, a health care provider maysend an electromagnetic signal which is received by the device in orderto activate the device, e.g., a wireless signal, a radio signal, etc.

In one set of embodiments, the device may include channels such asmicrofluidic channels, which may be used to deliver and/or receivefluids and/or other materials into or out of the skin, e.g., within thepooled region of fluid. In some cases, the microfluidic channels are influid communication with a substance transfer component that is used todeliver and/or receive fluids to or from the skin. For example, in oneset of embodiments, the device may include a hypodermic needle that canbe inserted into the skin, and fluid may be delivered into the skin viathe needle and/or received from the skin via the needle. The device mayalso include one or more microfluidic channels to contain fluid fordelivery to the needle, e.g., from a source of fluid, and/or to receivefluid from the skin, e.g., for delivery to on analytical chamber withinthe device, to a reservoir for later analysis, or the like.

In some cases, more than one chamber may be present within the device,and in some cases, some or all of the chambers may be in fluidiccommunication, e.g., via channels such as microfluidic channels. Invarious embodiments, a variety of chambers and/or channels may bepresent within the device, depending on the application. For example,the device may contain chambers for sensing an analyte, chambers forholding reagents, chambers for controlling temperature, chambers forcontrolling pH or other conditions, chambers for creating or bufferingpressure or vacuum, chambers for controlling or dampening fluid flow,mixing chambers, or the like.

Thus, in one set of embodiments the device may include a microfluidicchannel. As used herein, “microfluidic,” “microscopic,” “microscale,”the “micro-” prefix (for example, as in “microchannel”), and the likegenerally refers to elements or articles having widths or diameters ofless than about 1 mm, and less than about 100 microns (micrometers) insome cases. In some embodiments, larger channels may be used instead of,or in conjunction with, microfluidic channels for any of the embodimentsdiscussed herein. For example, channels having widths or diameters ofless than about 10 mm, less than about 9 mm, less than about 8 mm, lessthan about 7 mm, less than about 6 mm, less than about 5 mm, less thanabout 4 mm, less than about 3 mm, or less than about 2 mm may be used incertain instances. In some cases, the element or article includes achannel through which a fluid can flow. In all embodiments, specifiedwidths can be a smallest width (i.e. a width as specified where, at thatlocation, the article can have a larger width in a different dimension),or a largest width (i.e. where, at that location, the article has awidth that is no wider than as specified, but can have a length that isgreater). Thus, for instance, the microfluidic channel may have anaverage cross-sectional dimension (e.g., perpendicular to the directionof flow of fluid in the microfluidic channel) of less than about 1 mm,less than about 500 microns, less than about 300 microns, or less thanabout 100 microns. In some cases, the microfluidic channel may have anaverage diameter of less than about 60 microns, less than about 50microns, less than about 40 microns, less than about 30 microns, lessthan about 25 microns, less than about 10 microns, less than about 5microns, less than about 3 microns, or less than about 1 micron.

A “channel,” as used herein, means a feature on or in an article (e.g.,a substrate) that at least partially directs the flow of a fluid. Insome cases, the channel may be formed, at least in part, by a singlecomponent, e.g. an etched substrate or molded unit. The channel can haveany cross-sectional shape, for example, circular, oval, triangular,irregular, square or rectangular (having any aspect ratio), or the like,and can be covered or uncovered (i.e., open to the external environmentsurrounding the channel). In embodiments where the channel is completelycovered, at least one portion of the channel can have a cross-sectionthat is completely enclosed, and/or the entire channel may be completelyenclosed along its entire length with the exception of its inlet andoutlet.

A channel may have any aspect ratio, e.g., an aspect ratio (length toaverage cross-sectional dimension) of at least about 2:1, more typicallyat least about 3:1. at least about 5:1, at least about 10:1. etc. Asused herein, a “cross-sectional dimension,” in reference to a fluidic ormicrofluidic channel, is measured in a direction generally perpendicularto fluid flow within the channel. A channel generally will includecharacteristics that facilitate control over fluid transport, e.g.,structural characteristics and/or physical or chemical characteristics(hydrophobicity vs. hydrophilicity) and/or other characteristics thatcan exert a force (e.g., a containing force) on a fluid. The fluidwithin the channel may partially or completely fill the channel. In somecases the fluid may be held or confined within the channel or a portionof the channel in some fashion, for example, using surface tension(e.g., such that the fluid is held within the channel within a meniscus,such as a concave or convex meniscus). In an article or substrate, some(or all) of the channels may be of a particular size or less, forexample, having a largest dimension perpendicular to fluid flow of lessthan about 5 mm, less than about 2 mm, less than about 1 mm, less thanabout 500 microns, less than about 200 microns, less than about 100microns, less than about 60 microns, less than about 50 microns, lessthan about 40 microns, less than about 30 microns, less than about 25microns, less than about 10 microns, less than about 3 microns, lessthan about 1 micron, less than about 300 nm, less than about 100 nm,less than about 30 nm, or less than about 10 nm or less in some cases.In one embodiment, the channel is a capillary.

In some cases, the device may contain one or more chambers or reservoirsfor holding fluid. In some cases, the chambers may be in fluidiccommunication with one or more substance transfer components and/or oneor more microfluidic channels. For instance, the device may contain achamber for collecting fluid received from a subject (e.g., for storageand/or later analysis), a chamber for containing a fluid for delivery tothe subject (e.g., blood, saline, optionally containing drugs, hormones,vitamins, pharmaceutical agents, or the like), etc.

After receipt of the fluid into the device, the device, or a portionthereof, may be removed from the skin of the subject, e.g., by thesubject or by another person. For example, the entire device may beremoved, or a portion of the device containing the storage reservoir maybe removed from the device, and optionally replaced with another storagereservoir. Thus, for instance, in one embodiment, the device may containtwo or more modules, for example, a first module that is able to causereceiving of fluid from the skin into a storage reservoir, and a secondmodule containing the storage module. In some cases, the modulecontaining the storage reservoir may be removed from the device. Otherexamples of modules and modular systems are discussed below; otherexamples are discussed in U.S. Provisional Patent Application Ser. No.61/256,931, filed Oct. 30, 2009, entitled “Modular Systems forApplication to the Skin,” incorporated by reference herein in itsentirety.

The received fluid may then be sent to a clinical and/or laboratorysetting, e.g., for analysis. In some embodiments, the entire device maybe sent to the clinical and/or laboratory setting; in other embodiments,however, only a portion of the device (e.g., a module containing astorage reservoir containing the fluid) may be sent to the clinicaland/or laboratory setting. In some cases, the fluid may be shipped usingany suitable technique (e.g., by mail, by hand, etc.). In certaininstances, the subject may give the fluid to appropriate personnel at aclinical visit. For instance, a doctor may prescribe a device asdiscussed above for use by the subject, and at the next doctor visit,the subject may give the doctor the received fluid, e.g., containedwithin a device or module.

In some aspects, the device may contain an indicator. The indicator maybe used for determining a condition of a fluid contained within thedevice, e.g., within a fluid storage chamber or a fluid reservoir. Insome embodiments, the indicator may indicate one or more conditionsassociated with the introduction of fluid into the storage componentand/or one or more conditions associated with storage of fluid in thestorage component. For example, the indicator may indicate the conditionof blood or ISF within the device, e.g., as the device is beingtransported or shipped to a clinical or a laboratory setting. Theindicator may indicate the condition of the blood through any suitabletechnique, e.g., visually (such as with a color change), using adisplay, by producing a sound, etc. For instance, the indicator may havea display that is green if the fluid has not been exposed to certaintemperatures or if there is no adverse chemical reaction present withinthe fluid (e.g., a change in pH, growth of microorganisms, etc.), but isyellow or red if adverse conditions are or have been present (e.g.,exposure to temperatures that are too extreme, growth of microorganisms,etc.). In other embodiments, the display may display a visual message, asound may be produced by the device, or the like.

In some cases, the indicator may be activated upon the accessing offluid by the access component and/or introduction of fluid into thestorage component. In one set of embodiments, the indicator may beactivated upon the introduction of fluid within a fluid storagereservoir, upon activation of the device (e.g., to receive fluid from asubject, as discussed below), upon activation by a user (e.g., by thesubject, or another person), etc.

In some cases, the indicator may determine the condition of fluid withina fluid storage reservoir within the device using one or more suitablesensors, for example, pH sensors, temperature sensors (e.g.,thermocouples), oxygen sensors, or the like. For instance, a sensor maybe present within or proximate the fluid storage reservoir fordetermining the temperature of the fluid within the fluid storagereservoir. In some cases, for example, more than one sensor measurementmay be taken, e.g., at multiple points of time or even continuously. Insome cases, the indicator may also record the sensor determinations,e.g., for analysis or later study.

In certain embodiments, time information may be determined and/orrecorded by the indicator. For example, the time fluid enters a fluidstorage reservoir may be recorded, e.g., using a time/date stamp (e.g.,absolute time), and/or using the duration of time that fluid has beenpresent within the fluid storage reservoir. The time information mayalso be recorded in some embodiments.

As discussed, in one set of embodiments, information from sensors and/ortime information may be used to determine a condition of the fluidwithin the fluid storage reservoir. For example, if certain limits aremet or exceeded, the indicator may indicate that, as discussed above. Asa specific non-limiting example, if the temperature of the device is toolow (e.g., reaches 0° C.) or too high (e.g., reaches 100° C. or 37° C.),this may be displayed by a display on the indicator. Thus, fluid exposedto temperature extremes may be identified, e.g., as being problematic orspoiled. As a another non-limiting example, it may be desired to keepthe pH of fluid within the device within certain conditions, and if thepH is exceeded (e.g., too acidic or too basic), this may be displayed bya display on the indicator, for example, if the pH is less than 6 or 5,or greater than 8 or 9. In some cases, the time that fluid is presentwithin the device may be kept within certain limits as well, as anothercondition. For example, the indicator may indicate that fluid has beenpresent within the device for more than about 12 hours, more than about18 hours, or more than about 24 hours, which may indicate the fluid asbeing problematic, spoiled, etc.

In one set of embodiments, conditions such as these may also be combined(e.g., time and temperature). Thus, for example, fluid exposed to afirst temperature may be allowed to be present within the device for afirst time, while fluid exposed to a second temperature may be allowedto be present within the device for a second time, before the indicatordisplays this.

In some embodiments, the indicator may record and/or transmit sensor ortime information. This may be recorded and/or transmitted using anysuitable format. For instance, the information may be transmitted usinga wireless signal, a radio signal, etc., or recorded on any suitableelectronic media, e.g., on a microchip, flash drive, optically,magnetically, etc.

A variety of materials and methods, according to certain aspects of theinvention, can be used to form the device, e.g., microfluidic channels,chambers, etc. For example, various components of the invention can beformed from solid materials, in which the channels can be formed viamicromachining, film deposition processes such as spin crating andchemical vapor deposition, laser fabrication, photolithographictechniques, etching methods including wet chemical or plasma processes,and the like. See, for example, Scientific American, 248:44-55, 1983(Angell, et al).

In one set of embodiments, various components of the systems and devicesof the invention can be formed of a polymer, for example, an elastomericpolymer such as polydimethylsiloxane (“PDMS”), polytetrafluoroethylene(“PTFE” or Teflon®), or the like. For instance, according to oneembodiment, a microfluidic channel may be implemented by fabricating thefluidic system separately using PDMS or other soft lithographytechniques (details of soft lithography techniques suitable for thisembodiment are discussed in the references entitled “Soft Lithography,”by Younan Xia and George M. Whitesides, published in the Annual Reviewof Material Science, 1998, Vol. 28, pages 153-184, and “Soft Lithographyin Biology and Biochemistry,” by George M. Whitesides, Emanuele Ostuni,Shuichi Takayama, Xingyu Jiang and Donald E. Ingber, published in theAnnual Review of Biomedical Engineering, 2001, Vol. 3, pages 335-373;each of these references is incorporated herein by reference).

Other examples of potentially suitable polymers include, but are notlimited to, polyethylene terephthalate (PET), polyacrylate,polymethacrylate, polycarbonate, polystyrene, polyethylene,polypropylene, polyvinylchloride, cyclic olefin copolymer (COC),polytetrafluoroethylene, a fluorinated polymer, a silicone such aspolydimethylsiloxane, polyvinylidene chloride, bis-benzocyclobutene(“BCB”), a polyimide, a fluorinated derivative of a polyimide, or thelike. Combinations, copolymers, or blends involving polymers includingthose described above are also envisioned. The device may also be formedfrom composite materials, for example, a composite of a polymer and asemiconductor material.

In some embodiments, various components of the invention are fabricatedfrom polymeric and/or flexible and/or elastomeric materials, and can beconveniently formed of a hardenable fluid, facilitating fabrication viamolding (e.g. replica molding, injection molding, cast molding, etc.).The hardenable fluid can be essentially any fluid that can be induced tosolidify, or that spontaneously solidifies, into a solid capable ofcontaining and/or transporting fluids contemplated for use in and withthe fluidic network. In one embodiment, the hardenable fluid comprises apolymeric liquid or a liquid polymeric precursor (i.e. a “prepolymer”).Suitable polymeric liquids can include, for example, thermoplasticpolymers, thermoset polymers, waxes, metals, or mixtures or compositesthereof heated above their melting point. As another example, a suitablepolymeric liquid may include a solution of one or more polymers in asuitable solvent, which solution forms a solid polymeric material uponremoval of the solvent, for example, by evaporation. Such polymericmaterials, which can be solidified from, for example, a melt state or bysolvent evaporation, are well known to those of ordinary skill in theart. A variety of polymeric materials, many of which are elastomeric,are suitable, and are also suitable for forming molds or mold masters,for embodiments where one or both of the mold masters is composed of anelastomeric material. A non-limiting list of examples of such polymersincludes polymers of the general classes of silicone polymers, epoxypolymers, and acrylate polymers. Epoxy polymers are characterized by thepresence of a three-membered cyclic ether group commonly referred to asan epoxy group, 1,2-epoxide, or oxirane. For example, diglycidyl ethersof bisphenol A can be used, in addition to compounds based on aromaticamine, triazine, and cycloaliphatic backbones. Another example includesthe well-known Novolac polymers. Non-limiting examples of siliconeelastomers suitable for use according to the invention include thoseformed from precursors including the chlorosilanes such asmethylchlorosilanes, ethylchlorosilanes, phenylchlorosilanes, etc.

Silicone polymers are used in certain embodiments, for example, thesilicone elastomer polydimethylsiloxane. Non-limiting examples of PDMSpolymers include those sold under the trademark Sylgard by Dow ChemicalCo., Midland, Mich., and particularly Sylgard 182, Sylgard 184, andSylgard 186. Silicone polymers including PDMS have several beneficialproperties simplifying fabrication of the microfluidic structures of theinvention. For instance, such materials are inexpensive, readilyavailable, and can be solidified from a prepolymeric liquid via curingwith heat. For example, PDMSs are typically curable by exposure of theprepolymeric liquid to temperatures of about, for example, about 65° C.to about 75° C. for exposure times of, for example, about an hour. Also,silicone polymers, such as PDMS, can be elastomeric and thus may beuseful for forming very small features with relatively high aspectratios, necessary in certain embodiments of the invention. Flexible(e.g., elastomeric) molds or masters can be advantageous in this regard.

One advantage of forming structures such as microfluidic structures ofthe invention from silicone polymers, such as PDMS, is the ability ofsuch polymers to be oxidized, for example by exposure to anoxygen-containing plasma such as an air plasma, so that the oxidizedstructures contain, at their surface, chemical groups capable ofcross-linking to other oxidized silicone polymer surfaces or to theoxidized surfaces of a variety of other polymeric and non-polymericmaterials. Thus, components can be fabricated and then oxidized andessentially irreversibly scaled to other silicone polymer surfaces, orto the surfaces of other substrates reactive with the oxidized siliconepolymer surfaces, without the need for separate adhesives or othersealing means. In most cases, sealing can be completed simply bycontacting an oxidized silicone surface to another surface without theneed to apply auxiliary pressure to form the seal. That is, thepre-oxidized silicone surface acts as a contact adhesive againstsuitable mating surfaces. Specifically, in addition to beingirreversibly scalable to itself, oxidized silicone such as oxidized PDMScan also be scaled irreversibly to a range of oxidized materials otherthan itself including, for example, glass, silicon, silicon oxide,quartz, silicon nitride, polyethylene, polystyrene, glassy carbon, andepoxy polymers, which have been oxidized in a similar fashion to thePDMS surface (for example, via exposure to an oxygen-containing plasma).Oxidation and sealing methods useful in the context of the presentinvention, as well as overall molding techniques, are described in theart, for example, in an article entitled “Rapid Prototyping ofMicrofluidic Systems and Polydimethylsiloxane,” Anal. Chem., 70:474-480,1998 (Duffy el al.), incorporated herein by reference.

Another advantage to forming microfluidic structures of the invention(or interior, fluid-contacting surfaces) from oxidized silicone polymersis that these surfaces can be much more hydrophilic than the surfaces oftypical elastomeric polymers (where a hydrophilic interior surface isdesired). Such hydrophilic channel surfaces can thus be more easilyfilled and wetted with aqueous solutions than can structures comprisedof typical, unoxidized elastomeric polymers or other hydrophobicmaterials.

As described herein, any of a variety of signaling or display methods,associated with analyses, can be provided including signaling visually,by smell, sound, feel, taste, or the like, in one set of embodiments.Signal structures or generators include, but are not limited to,displays (visual, LED, light, etc.), speakers, chemical-releasingchambers (e.g., containing a volatile chemical), mechanical devices,heaters, coolers, or the like. In some cases, the signal structure orgenerator may be integral with the device (e.g., integrally connectedwith a substance transfer component for application to the skin of thesubject, e.g., such as a needle or a microneedle), or the signalstructure may not be integrally connected with the substance transfercomponent. As used herein, a “signal structure” or a “signal generator”is any apparatus able to generate a signal that is related to acondition of a medium. For example, the medium may be a bodily fluid,such as blood or interstitial fluid.

In some embodiments, signaling methods such as these may be used toindicate the presence and/or concentration of an analyte determined bythe sensor, e.g., to the subject, and/or to another entity, such asthose described below. Where a visual signal is provided, it can beprovided in the form of change in opaqueness, a change in intensity ofcolor and/or opaqueness, or can be in the form of a message (e.g.,numerical signal, or the like), an icon (e.g., signaling by shape orotherwise a particular medical condition), a brand, logo, or the like.For instance, in one embodiment, the device may include a display. Awritten message such as “take next dose,” or “glucose level is high” ora numerical value might be provided, or a message such as “toxin ispresent.” These messages, icons, logos, or the like can be provided asan electronic read-out by a component of a device and/or can bedisplayed as in inherent arrangement of one or more components of thedevice.

In some embodiments, a device is provided where the device determines aphysical condition of a subject and produces a signal related to thecondition that can be readily understood by the subject (e.g., byprovision of a visual “OK” signal as described above) or can be designedso as not to be readily understandable by a subject. Where not readilyunderstandable, the signal can take a variety of forms. In one form, thesignal might be a series of letters or numbers that mean nothing to thesubject (e.g., A1278CDQ) which would have meaning to a medicalprofessional or the like (and/or be decodable by the same, e.g., withreference to a suitable decoder) and can be associated with a particularphysiological condition. Alternatively, a signal in the form of bar codecan be provided by a device such that, under a particular condition orset of conditions the bar code appears and/or disappears, or changes,and can be read by a bar code reader to communicate information aboutthe subject or analyte. In another embodiment, the device can bedesigned such that an ultraviolet signal is produced, or a signal thatcan be read only under ultraviolet light (e.g., a simple spot or patch,or any other signal such as a series of number, letters, barcode,message, or the like that can be readily understandable or not readilyunderstandable by a subject) can be provided. The signal may beinvisible to the human eye but, upon application UV light or otherexcitation energy, may be readable. The signal can be easily readable orunderstandable by a user via visual observation, or with other sensoryactivity such as smell, feel, etc. In another set of embodimentsequipment as described above may be needed to determine a signalprovided by the device, such as equipment in a clinical setting, etc. Insome cases, the device is able to transmit a signal indicative of theanalyte to a receiver, e.g., as a wireless signal, a radio signal, etc.

In some embodiments, quantitative and/or qualitative analyses can beprovided by a device. That is, the device in some cases may provideanalyses that allow “yes/no” tests or the like, or tests that provideinformation on the quantity, concentration, or level of a particularanalyte or analytes. Display configurations can be provided by theinvention that reflect the amount of a particular analyte present in asubject at a particular point in time, or any other variable (presenceof analysis over time, type of analyte, etc.) display configurations cantake a variety of forms. In one example, a dial can be provided, similarto that of a speedometer with a series of level indications (e.g.,numbers around the dial) and a “needle” or other device that indicates aparticular level. In other configurations, a particular area of thedevice (e.g., on a display) can exist that is filled in to a greater orlesser extent depending upon the presence and/or quantity of aparticular analyte present, e.g., in the form of a bar graph. In anotherarrangement a “color wheel” can be provided where the amount of aparticular analyte present can control which colors of the wheel arevisible. Or, different analytes can cause different colors of a wheel ordifferent bars of a graph to become visible or invisible in a multipleanalyte analysis. Multiple-analyte quantitative analyses can bereflected in multiple color wheels, a single color wheel with differentcolors per analyte where the intensity of each color reflects the amountof the analyte, or, for example, a plurality of bar graphs where eachbar graph is reflective of a particular analyte and the level of the bar(and/or degree to which an area is filled in with visible color or othervisible feature) is reflective of the amount of the analyte. As with allembodiments here, whatever signal is displayed can be understandable ornot understandable to any number of participants. For example, it can beunderstandable to a subject or not understandable to a subject. Wherenot understandable it might need to be decoded, read electronically, orthe like. Where read electronically, for example, a device may provide asignal that is not understandable to a subject or not even visible orotherwise able to be sensed by a subject, and a reader can be providedadjacent or approximate the device that can provide a visible signalthat is understandable or not understandable to the subject, or cantransmit a signal to another entity for analysis.

In connection with any signals associated with any analyses describedherein, another, potentially related signal or other display (or smell,taste, or the like) can be provided which can assist in interpretingand/or evaluating the signal. In one arrangement, a calibration orcontrol is provided proximate (or otherwise easily comparable with) asignal, e.g., a visual calibration/control or comparator next to orclose to a visual signal provided by a device and/or implanted agents,particles, or the like.

A visual control or reference can be used with another sensory signal,such as that of smell, taste, temperature, itch. etc. Areference/control and/or experimental confirmation component can beprovided, to be used in connection with an in-skin test or vice versa.References/indicators can also be used to indicate the state of life ofa device, changing color or intensity and/or changing in anothersignaling aspect as the device changes relative to its useful life, sothat a user can determine when the device should no longer be reliedupon and/or removed. For certain devices, an indicator or control can beeffected by adding analyte to the control (e.g., from a source outsideof the source to be determine) to confirm operability of the deviceand/or to provide a reference against which to measure a signal of thedevice. For example, a device can include a button to be tapped by auser which will allow an analyte from a reservoir to transfer to anindicator region to provide a signal, to demonstrate operability of thedevice and/or provide a comparator for analysis.

Many of the embodiments described herein involve a quantitative analysisand related signal, i.e., the ability to determine the relative amountor concentration of an analyte in a medium. This can be accomplished ina variety of ways. For example, where an agent (e.g. a binding partnerattached to a nanoparticle) is used to capture and analyze an analyte,the agent can be provided in a gradient in concentration across asensing region of the device. Or a sensing region can include a membraneor other apparatus through which analyte is required to flow or passprior to capture and identification, and the pathway for analyte travelcan vary as a function of position of display region. For example, amembrane can be provided across a sensing region, through which analytemust pass prior to interacting with a layer of binding and/or signalingagent, and the membrane may vary in thickness laterally in a directionrelated to “bar graph” readout. Where a small amount of analyte ispresent, it may pass through the thinner portion but not the thickerportion of the membrane, but where a larger amount is present, it maypass across a thicker portion. The boundary (where one exists) between aregion through which analyte passes, and one through which it does notcompletely pass, can define the “line” of the bar graph. Other ways ofachieving the same or a similar result can include varying theconcentration of a scavenger or transporter of the analyte, or anintermediate reactive species (between analyte and signaling event),across a membrane or other article, gradient in porosity or selectivityof the membrane, ability to absorb or transport sample fluid, or thelike. These principles, in combination with other disclosure herein, canbe used to facilitate any or all of the quantitative analyses describedherein.

In one set of embodiments, a subject having a condition such as aphysiological condition to be analyzed (or other user, such as medicalpersonnel) reads and/or otherwise determines a signal from a device. Forexample, the device may transmit a signal indicative of a condition ofthe subject and/or the device. Alternatively, or in addition, a signalproduced by a device can be acquired in the form of a representation(e.g. a digitized signal, or the like) and transmitted to another entityfor analysis and/or action. For example, a signal can be produced by adevice, e.g., based on a sensor reading of an analyte, based on fluiddelivered and/or received from the skin, based on a condition of thedevice, or the like. The signal may represent any suitable data orimage. For example, the signal may represent the presence and/orconcentration of an analyte in fluid received from a subject, the amountof fluid received from a subject and/or delivered to the subject, thenumber of times the device has been used, the battery life of thedevice, the amount of vacuum left in the device, the cleanliness orsterility of the device, the identity of the device (e.g., wheremultiple devices are given unique identification numbers, to preventcounterfeiting, accidental exchange of equipment to incorrect users,etc.), or the like. For instance, in one set of embodiments, an image ofthe signal (e.g., a visual image or photograph) can be obtained andtransmitted to a different entity (for example, a user can take a cellphone picture of a signal generated by the device and send it, via cellphone, the other entity).

The other entity that the signal is transmitted to can be a human (e.g.,a clinician) or a machine. In some cases, the other entity may be ableto analyze the signal and take appropriate action. In one arrangement,the other entity is a machine or processor that analyzes the signal andoptionally sends a signal back to the device to give direction as toactivity (e.g., a cell phone can be used to transmit an image of asignal to a processor which, under one set of conditions, transmits asignal back to the same cell phone giving direction to the user, ortakes other action). Other actions can include automatic stimulation ofthe device or a related device to dispense a medicament orpharmaceutical, or the like. The signal to direct dispensing of apharmaceutical can take place via the same used to transmit the signalto the entity (e.g., cell phone) or a different vehicle or pathway.Telephone transmission lines, wireless networks, Internet communication,and the like can also facilitate communication of this type.

As one specific example, a device may be a glucose monitor. As signalmay be generated by the device and an image of the signal captured by acell phone camera and then transmitted via cell phone to a clinician.The clinician may then determine that the glucose (or e.g., insulin)level is appropriate or inappropriate and send a message indicating thisback to the subject via cell phone.

Information regarding the analysis can also be transmitted to the sameor a different entity, or a different location simply by removing thedevice or a portion of the device from the subject and transferring itto a different location. For example, a device can be used in connectionwith a subject to analyze presence and/or amount of a particularanalyte. At some point after the onset of use, the device, or a portionof the device carrying a signal or signals indicative of the analysts oranalyses, can be removed and, e.g., attached to a record associated withthe subject. As a specific example, a patch or other device can be wornby a subject to determine presence and/or amount of one or more analytesqualitatively, quantitatively, and/or over time. The subject can visit aclinician who can remove the patch (or other device) or a portion of thepatch and attach it to a medical record associated with the subject.

According to various sets of embodiments, the device may be used once,or multiple times, depending on the application. For instance, obtainingsamples for sensing, according to certain embodiments of the invention,can be done such that sensing can be carried out continuously,discretely, or a combination of these. For example, where a bodily fluidsuch as blood or interstitial fluid is accessed for determination of onanalyte, fluid can be accessed discretely (i.e., as a single dose, onceor multiple times), or continuously by creating a continuous flow offluid which can be analyzed once or any number of times. Additionally,testing can be carried out once, at a single point in time, or atmultiple points in time, and/or from multiple samples (e.g., at multiplelocations relative to the subject).

Alternatively or in addition, testing can be carried out continuouslyover any number of points in time involving one or any number oflocations relative to the subject or other multiple samples. As anexample, one bolus or isolated sample, of fluid such as interstitialfluid can be obtained. From that fluid a test can be carried out todetermine whether a particular analyte or other agent exists in thefluid. Alternatively, two or more tests can be carried out involvingthat quantity of fluid to determine the presence and/or quantity of twoor more analytes, and any number of such tests can be carried out. Testsinvolving that quantity of fluid can be carried out simultaneously orover a period of time. For example, a test for a particular analyte canbe carried out at various points in time to determine whether the resultchanges over time, or different analytes can be determined at differentpoints in time.

In another example, a needle or a microneedle, or other device(s) can beused to access a fluid of a subject such as interstitial fluid. Fluidcan be drawn to a point of analysis and analyzed in any manner describedherein. For example, an analysis can be carried out once, to determinethe presence and/or quantity of a single analyte, or a number of testscan be carried out. From a single sample of fluid, a particular test ornumber of tests can be carried out essentially simultaneously, oranalyses can be carried out over time. Moreover, fluid can be drawncontinuously from the subject and one or more tests can be carried outof any number of points in time. A variety of reasons for carrying outone or more tests over the course of time exists, as would be understoodby those of ordinary skill in the art. One such reason is to determinewhether the quantity or another characteristic of an analyte is constantin a subject, or changes over time. A variety of specific techniques forcontinuous and/or discrete testing will be described herein.

In one set of embodiments, one or more materials, such as particles, aredelivered to the skin. Examples of suitable materials include, but arenot limited to, particles such as microparticles or nanoparticles, achemical, a drug or a therapeutic agent, a diagnostic agent, a carrier,or the like. The particles may be, for example, nanoparticles ormicroparticles, and in some cases, the particles may be anisotropicparticles. In some cases, a plurality of particles may be used, and insome cases, some, or substantially all, of the particles may be thesame. For example, at least about 10%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, at least about 95%, or at leastabout 99% of the particles may have the same shape, and/or may have thesame composition.

The particles may be used for a variety of purposes. For instance, theparticles may contain a diagnostic agent or a reaction entity able tointeract with and/or associate with an analyte, or another reactionentity, or other particles. Such particles may be useful, for example,to determine one or more analytes, such as a marker of a disease state,as discussed below. As another example, the particles may contain a drugor a therapeutic agent, positioned on the surface and/or internally ofthe particles, which may be released by the particles and delivered tothe subject. Specific examples of these and other embodiments arediscussed in detail below.

In some cases, materials such as particles may become embedded withinthe skin, for example, due to physical properties of the materials(e.g., size, hydrophobicity, etc.). Thus, in some cases, a depot ofmaterial may be formed within the skin, and the depot may be temporaryor permanent. For instance, materials within the depot may eventuallydegrade (e.g., if the material is biodegradable), enter the bloodstream,or be sloughed off to the environment, e.g., as the cells of the dermisdifferentiate to form new epidermis and accordingly push the materialtowards the surface of the skin. Thus, the depot of material may bepresent within the subject on a temporary basis (e.g., on a time scaleof days or weeks), in certain instances.

As mentioned, certain aspects of the present invention are generallydirected to particles such as anisotropic particles or colloids whichcan be used in a wide variety of applications. For instance, theparticles may be present within the skin, or externally of the skin,e.g., in a device on the surface of the skin. The particles may includemicroparticles and/or nanoparticles. As discussed above, a“microparticle” is a particle having an average diameter on the order ofmicrometers (i.e., between about 1 micrometer and about 1 mm), while a“nanoparticle” is a particle having an average diameter on the order ofnanometers (i.e., between about 1 nm and about 1 micrometer. Theparticles may be spherical or non-spherical, in some cases. For example,the particles may be oblong or elongated, or have other shapes such asthose disclosed in U.S. patent application Ser. No. 11/851,974, filedSep. 7, 2007, entitled “Engineering Shape of Polymeric Micro- andNanoparticles,” by S. Mitragotri, et al.; International PatentApplication No. PCT/US2007/077889, filed Sep. 7, 2007, entitled“Engineering Shape of Polymeric Micro- and Nanoparticles,” by S.Mitragotri, et al., published as WO 2008/031035 on Mar. 13, 2008; U.S.patent application Ser. No. 11/272,194, filed Nov. 10, 2005, entitled“Multi-phasic Nanoparticles,” by J. Lahann, et al., published as U.S.Patent Application Publication No. 2006/0201390 on Sep. 14, 2006; orU.S. patent application Ser. No. 11/763,842, filed Jun. 15, 2007,entitled “Multi-Phasic Bioadhesive Nan-Objects as Biofunctional Elementsin Drug Delivery Systems,” by J. Lahann, published as U.S. PatentApplication Publication No. 2007/0237800 on Oct. 11, 2007, each of whichis incorporated herein by reference. Other examples of particles can beseen in U.S. patent application Ser. No. 11/272,194, filed Nov. 10,2005, entitled “Multi-phasic Nanoparticles,” by J. Lahann, et al.,published as U.S. Patent Application Publication No. 2006/0201390 onSep. 14, 2006; U.S. patent application Ser. No. 11/763,842, filed Jun.15, 2007, entitled “Multi-Phasic Bioadhesive Nan-Objects asBiofunctional Elements in Drug Delivery Systems,” by J. Lahann,published as U.S. Patent Application Publication No. 2007/0237800 onOct. 11, 2007; or U.S. Provisional Patent Application Ser. No.61/058,796, filed Jun. 4, 2008, entitled “Compositions and Methods forDiagnostics, Therapies, and Other Applications,” by D. Levinson, each ofwhich is incorporated herein by reference. Other examples of particlescan be seen in U.S. patent application Ser. No. 11/272,194, filed Nov.10, 2005, entitled “Multi-phasic Nanoparticles,” by J. Lahann, et al.,published as U.S. Patent Application Publication No. 2006/0201390 onSep. 14, 2006; U.S. patent application Ser. No. 11/763,842, filed Jun.15, 2007, entitled “Multi-Phasic Bioadhesive Nan-Objects asBiofunctional Elements in Drug Delivery Systems,” by J. Lahann,published as U.S. Patent Application Publication No. 2007/0237800 onOct. 11, 2007; or U.S. Provisional Patent Application Ser. No.61/058,796, filed Jun. 4, 2008, entitled “Compositions and Methods forDiagnostics, Therapies, and Other Applications,” by D. Levinson, each ofwhich is incorporated herein by reference.

In some cases, a pooled region of fluid, such as a suction blister, maybe formed in the skin to facilitate delivery and/or receiving of fluidfrom the skin. Thus, certain aspects of the present invention aregenerally directed to the creation of suction blisters or other pooledregions of fluid within the skin. In one set of embodiments, a pooledregion of fluid can be created between the dermis and epidermis of theskin. Suction blisters or other pooled regions may form in a manner suchthat the suction blister or other pooled region is not significantlypigmented in some cases, since the basal layer of the epidermis containsmelanocytes, which are responsible for producing pigments. Such regionscan be created by causing the dermis and the epidermis to at leastpartially separate, and as will be discussed below, a number oftechniques can be used to at least partially separate the dermis fromthe epidermis.

In one technique, a pool of interstitial fluid is formed between layersof skin of a subject and, after forming the pool, fluid is drawn fromthe pool by accessing the fluid through a layer of skin, for example,puncturing the outer layer of skin with a microneedle. Specifically, forexample, a suction blister can be formed and then the suction blistercan be punctured and fluid can be drawn from the blister. In anothertechnique, an interstitial region can be accessed and fluid drawn fromthat region without first forming a pool of fluid via a suction blisteror the like. For example, a microneedle or microneedles can be appliedto the interstitial region and fluid can be drawn there from.

Pooled regions of fluids may be formed on any suitable location withinthe skin of a subject. Factors such as safety or convenience may be usedto select a suitable location, as (in humans) the skin is relativelyuniform through the body, with the exception of the hands and feet. Asnon-limiting examples, the pooled region may be formed on an arm or aleg, on the chest, abdomen, or the back of the subject, or the like. Thesize of the pooled region of fluid that is formed in the skin and/or theduration that the pooled region lasts within the skin depends on avariety of factors, such as the technique of creating the pooled region,the size of the pooled region, the size of the region of skin to whichthe technique is applied, the amount of fluid received from the pooledregion (if any), any materials that are delivered into the pooledregion, or the like. For example, if vacuum is applied to the skin tocreate a suction blister, the vacuum applied to the skin, the durationof the vacuum, and/or the area of the skin affected may be controlled tocontrol the size and/or duration of the suction blister. In someembodiments, it may be desirable to keep the pooled regions relativelysmall, for instance, to prevent an unsightly visual appearance, to allowfor greater sampling accuracy (due to a smaller volume of material), orto allow for more controlled placement of particles within the skin. Forexample, the volume of the pooled region may be kept to less than about2 ml or less than about 1 ml in certain cases, or the average diameterof the pooled region (i.e., the diameter of a circle having the samearea as the pooled region) may be kept to less than about 5 cm, lessthan about 4 cm, less than about 3 cm, less than about 2 cm, less thanabout 1 cm, less man about 5 mm, less than about 4 mm, less than about 3mm, less than about 2 mm, or less than about 1 mm.

A variety of techniques may be used to cause pooled regions of fluid toform within the skin. In one set of embodiments, vacuum is applied tocreate a suction blister, or otherwise used to collect interstitialfluid from a subject. In other embodiments, however, other methods maybe used to create as a pooled region of fluid within the skin besides,or in addition to, the use of vacuum. When vacuum (i.e., the amount ofpressure below atmospheric pressure, such that atmospheric pressure hasa vacuum of 0 mmHg, i.e., the pressure is gauge pressure rather thanabsolute pressure) is used to at least partially separate the dermisfrom the epidermis to cause the pooled region to form, the pooled regionof fluid thus formed can be referred to as a suction blister. Forexample, vacuums of at least about 50 mmHg, at least about 100 mmHg, atleast about 150 mmHg, at least about 200 mmHg, at least about 250 mmHg,at least about 300 mmHg, at least about 350 mmHg, at least about 400mmHg, at least about 450 mmHg, at least about 500 mmHg, at least about550 mmHg, at least about 600 mmHg, at least about 650 mmHg, at leastabout 700 mmHg, or at least about 750 mmHg may be applied to the skin,e.g., to cause a suction blister and/or to collect interstitial fluidfrom a subject (as discussed, these measurements are negative relativeto atmospheric pressure. Different amounts of vacuum may be applied todifferent subjects in some cases, for example, due to differences in thephysical characteristics of the skin of the subjects.

The vacuum may be applied to any suitable region of the skin, and thearea of the skin to which the vacuum may be controlled in some cases.For instance, the average diameter of the region to which vacuum isapplied may be kept to less than about 5 cm, less than about 4 cm, lessthan about 3 cm, less than about 2 cm, less than about 1 cm, less thanabout 5 mm, less than about 4 mm, less than about 3 mm, less, than about2 mm, or less than about 1 mm. In addition, such vacuums may be appliedfor any suitable length of time at least sufficient to cause at leastsome separation of the dermis from the epidermis to occur. For instance,vacuum may be applied to the skin for at least about 1 min, at leastabout 3 min, at least about 5 min, at least about 10 min, at least about15 min, at least about 30 min, at least about 1 hour, at least about 2hours, at least about 3 hours, at least about 4 hours, etc. Examples ofdevices suitable for creating such suction blisters are discussed inmore detail below. In other cases, however, bodily fluids such as bloodor interstitial fluid may be received from the skin using vacuum withoutthe creation of a suction blister. Other non-limiting fluids includesaliva, sweat, tears, mucus, plasma, lymph, or the like.

Other methods besides vacuum may be used to cause such separation tooccur. For example, in another set of embodiments, heat may be used. Forinstance, a portion of the skin may be heated to al least about 40° C.,at least about 50° C., at least about 55° C., or at least about 60° C.,using any suitable technique, to cause such separation to occur. Theskin may be heated, for instance, using an external heat source (e.g.,radiant heat or a heated water bath), a chemical reaction,electromagnetic radiation (e.g., microwave radiation, infraredradiation, etc.), or the like. In some cases, the radiation may befocused on a relatively small region of the skin, e.g., to at leastpartially spatially contain the amount of heating within the skin thatoccurs.

In yet another set of embodiments, a separation chemical may be appliedto the skin to at least partially cause separation of the dermis and theepidermis to occur. Non-limiting examples of such separation chemicalsinclude proteases such as trypsin, purified human skin tryptase, orcompound 48/80. Separation compounds such as these are commerciallyavailable from various sources. The separation chemical may be applieddirectly to the skin, e.g., rubbed into the surface of the skin, or insome cases, the separation chemical can be delivered into the subject,for example, between the epidermis and dermis of the skin. Theseparation chemical can, for example, be injected in between the dermisand the epidermis.

Another example of a separation chemical is a blistering agent, such aspit viper venom or blister beetle venom. Non-limiting examples ofblistering agents include phosgene oxime, Lewisite, sulfur mustards(e.g., mustard gas or 1,5-dichloro-3-thiapentane,1,2-bis(2-chloroethylthio)ethane, 1,3-bis(2-chloroethylthio)-n-propane,1,4-bis(2-chloroethylthio)-n-butane,1,5-bis(2-chloroethylthio)-n-pentane, 2-chloroethylchloromethylsulfide,bis(2-chloroethyl)sulfide, bis(2-chloroethylthio)methane,bis(2-chloroethylthiomethyl)ether, or bis(2-chloroethylthioethyl)ether),or nitrogen mustards (e.g., bis(2-chloroethyl)ethylamine,bis(2-chloroethyl)methylamine, or tris(2-chloroethyl)amine).

In still another set of embodiments, a device may be inserted into theskin and used to mechanically separate the epidermis and the dermis, forexample, a wedge or a spike. Fluids may also be used to separate theepidermis and the dermis, in yet another set of embodiments. Forexample, saline or another relatively inert fluid may be injected intothe skin between the epidermis and the dermis to cause them to at leastpartially separate.

These and/or other techniques may also be combined, in still otherembodiments. For example, in one embodiment, vacuum and heat may beapplied to the skin of a subject, sequentially and/or simultaneously, tocause such separation to occur. As a specific example, in oneembodiment, vacuum is applied while the skin is heated to a temperatureof between about 40° C. and about 50° C.

One aspect of the present invention is directed to an adaptor able toposition a device of the invention in apparatuses designed to containVacutainer™ tubes or Vacuette™ tubes. In some cases, the Vacutainer orVacuette tube sizes have a maximum length of no more than about 75 mm orabout 100 mm and a diameter of no more than about 16 mm or about 13 mm.In some cases, the adaptor may be able to immobilize a device of theinvention therein, e.g., for subsequent use or processing. In somecases, as previously discussed, devices of the invention may have alargest lateral dimension of no more than about 50 mm, and/or a largestvertical dimension, extending from the skin of the subject when thedevice is applied to the subject, of no more than about 10 mm. Anexample of such a device is shown in FIG. 9, with device 800 containedwithin adapter 850. The device may contained within the adaptor usingany suitable technique, e.g., using clips, springs, braces, bands, orthe application of force to the device present within the adaptor.

In another aspect, the present invention is directed to a kit includingone or more of the compositions previously discussed, e.g., a kitincluding a device for the delivery and/or receiving of fluid from theskin, a kit including a device able to create a pooled region of fluidwithin the skin of a subject, a kit including a device able to determinea fluid, or the like. An example of a kit containing more than onedevice of the invention is illustrated in FIG. 2D, with kit 150containing devices 152. A “kit,” as used herein, typically defines apackage or an assembly including one or more of the compositions ordevices of the invention, and/or other compositions or devicesassociated with the invention, for example, as previously described. Forexample, in one set of embodiments, the kit may include a device and oneor more compositions for use with the device. Each of the compositionsof the kit, if present, may be provided in liquid form (e.g., insolution), or in solid form (e.g., a dried powder). In certain cases,some of the compositions may be constitutable or otherwise processable(e.g., to an active form), for example, by the addition of a suitablesolvent or other species, which may or may not be provided with the kit.Examples of other compositions or components associated with theinvention include, but are not limited to, solvents, surfactants,diluents, salts, buffers, emulsifiers, chelating agents, fillers,antioxidants, binding agents, bulking agents, preservatives, dryingagents, antimicrobials, needles, syringes, packaging materials, tubes,bottles, flasks, beakers, dishes, frits, fillers, rings, clamps, wraps,patches, containers, tapes, adhesives, and the like, for example, forusing, administering, modifying, assembling, storing, packaging,preparing, mixing, diluting, and/or preserving the compositionscomponents for a particular use, for example, to a sample and/or asubject.

A kit of the invention may, in some cases, include instructions in anyform that are provided in connection with the compositions of theinvention in such a manner that one of ordinary skill in the art wouldrecognize that the instructions are to be associated with thecompositions of the invention. For instance, the instructions mayinclude instructions for the use, modification, mixing, diluting,preserving, administering, assembly, storage, packaging, and/orpreparation of the compositions and/or other compositions associatedwith the kit. In some cases, the instructions may also includeinstructions for the delivery and/or administration of the compositions,for example, for a particular use, e.g., to a sample and/or a subject.The instructions may be provided in any form recognizable by one ofordinary skill in the art as a suitable vehicle for containing suchinstructions, for example, written or published, verbal, audible (e.g.,telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) orelectronic communications (including Internet or web-basedcommunications), provided in any manner.

In some embodiments, the present invention is directed to methods ofpromoting one or more embodiments of the invention as discussed herein.As used herein, “promoted” includes all methods of doing businessincluding, but not limited to, methods of selling, advertising,assigning, licensing, contracting, instructing, educating, researching,importing, exporting, negotiating, financing, loaning, trading, vending,reselling, distributing, repairing, replacing, insuring, suing,patenting, or the like that are associated with the systems, devices,apparatuses, articles, methods, compositions, kits, etc. of theinvention as discussed herein. Methods of promotion can be performed byany party including, but not limited to, personal parties, businesses(public or private), partnerships, corporations, trusts, contractual orsub-contractual agencies, educational institutions such as colleges anduniversities, research institutions, hospitals or other clinicalinstitutions, governmental agencies, etc. Promotional activities mayinclude communications of any form (e.g., written, oral, and/orelectronic communications, such as, but not limited to, e-mail,telephonic, Internet, Web-based, etc.) that are clearly associated withthe invention.

In one set of embodiments, the method of promotion may involve one ormore instructions. As used herein, “instructions” can define a componentof instructional utility (e.g., directions, guides, warnings, labels,notes, FAQs or “frequently asked questions,” etc.), and typicallyinvolve written instructions on or associated with the invention and/orwith the packaging of the invention. Instructions can also includeinstructional communications in any form (e.g., oral, electronic,audible, digital, optical, visual, etc.), provided in any manner suchthat a user will clearly recognize that the instructions are to beassociated with the invention, e.g., as discussed herein.

The following documents are incorporated herein by reference: U.S.Provisional Patent Application Ser. No. 61/058,796, filed Jun. 4, 2008,entitled “Compositions and Methods for Diagnostics, Therapies, and OtherApplications”; U.S. Provisional Patent Application Ser. No. 61/163,791,filed Mar. 26, 2009, entitled “Composition and Methods for RapidOne-Step Diagnosis”; U.S. Provisional Patent Application Ser. No.61/163,793, filed Mar. 26, 2009, entitled “Compositions and Methods forDiagnostics, Therapies, and Other Applications”; U.S. patent applicationSer. No. 12/478,756, filed Jun. 4, 2009, entitled “Compositions andMethods for Diagnostics, Therapies, and Other Applications”;International Patent Application No. PCT/US09/046333, filed Jun. 4,2009, entitled “Compositions and Methods for Diagnostics, Therapies, andOther Applications”; U.S. Provisional Patent Application Ser. No.61/163,710, filed Mar. 26, 2009, entitled “Systems and Methods forCreating and Using Suction Blisters or Other Pooled Regions of Fluidwithin the Skin”; U.S. Provisional Patent Application Ser. No.61/163,733, filed Mar. 26, 2009, entitled “Determination of Tracerswithin Subjects”; U.S. Provisional Patent Application Ser. No.61/163,750, filed Mar. 26, 2009, entitled “Monitoring of Implants andOther Devices”; U.S. Provisional Patent Application Ser. No. 61/154,632,filed Mar. 2, 2009, entitled “Oxygen Sensor”; and U.S. ProvisionalPatent Application Ser. No. 61/269,436, filed Jun. 24, 2009, entitled“Devices and Techniques associated with Diagnostics, Therapies, andOther Applications, Including Skin-Associated Applications.” Alsoincorporated by reference herein are U.S. Provisional Patent ApplicationSer. No. 61/263,882, filed Nov. 24, 2009, entitled “Patient-EnactedSampling Technique”; U.S. Provisional Patent Application Ser. No.61/294,543, filed Jan. 13, 2010, entitled “Blood Sampling Device andMethod”; U.S. patent application Ser. No. 12/716,222, filed Mar. 2,2010, entitled “Oxygen Sensor,” by Levinson, et al.; U.S. patentapplication Ser. No. 12/716,233, filed Mar. 2, 2010, entitled “Systemsand Methods for Creating and Using Suction Blisters or Other PooledRegions of Fluid within the Skin,” by Levinson, et al.; U.S. patentapplication Ser. No. 12/716,226, filed Mar. 2, 2010, entitled“Techniques and Devices Associated with Blood Sampling,” by Levinson, etal.; and U.S. patent application Ser. No. 12/716,229, filed Mar. 2,2010, entitled “Devices and Techniques Associated with Diagnostics,Therapies, and Other Applications, Including Skin-AssociatedApplications,” by Bernstein, et al; U.S. Provisional Patent ApplicationSer. No. 61/256,880, filed Oct. 30, 2009, entitled “Systems and Methodsfor Altering or Masking Perception of Treatment of a Subject,” byChickering, et al.; U.S. Provisional Patent Application Ser. No.61/236,874, filed Oct. 30, 2009, entitled “Systems and Methods forApplication to Skin and Control of Use Thereof,” by Benstein, et al.;U.S. Provisional Patent Application Ser. No. 61/256,871, filed Oct. 30,2009, entitled “Packaging Systems and Methods for Devices Applied to theSkin,” by Bernstein, et al.; U.S. Provisional Patent Application Ser.No. 61/334,533, filed May 13, 2010, entitled “Blood Sampling Device andMethod,” by Chickering, et al.; U.S. Provisional Patent Application Ser.No. 61/334,529, filed May 13, 2010, entitled “Sampling DeviceInterfaces,” by Chickering, et al.; and U.S. patent application Ser. No.13/006,165, filed Jan. 13, 2011, entitled “Sampling Device Interfaces”by Chickering, et al.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning: as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

What is claimed is: 1-37. (canceled)
 38. A microneedle structurecomprising: a first plurality of microneedles that each includes a baseportion and a penetrating portion, the base portions of the firstplurality of microneedles being arranged at the periphery of a firstclosed loop lying in a plane, the penetrating portions of the firstplurality of microneedles each being bent upwardly from the plane andextending at a respective angle away from the plane of the first closedloop, wherein the penetrating portions each have an approximatelytrapezoid-shaped lateral cross section, and wherein the penetratingportions each include a proximal portion and an opposing distal portion,the proximal portion extending from the base portion and the distalportion comprising a point.
 39. The structure of claim 38, wherein thefirst closed loop is a circle, and the penetrating portions extendperpendicularly away from the plane.
 40. The structure of claim 38,further comprising: a second plurality of microneedles that eachincludes a base portion and a penetrating portion, the base portions ofthe second plurality of microneedles being arranged at a periphery of asecond closed loop lying in the plane, the second closed loop beinglarger than, and surrounding, the first closed loop, the penetratingportions of the second plurality of microneedles each extending at arespective angle away from the plane of the second closed loop, whereinthe first and second closed loops are concentric circles.
 41. Thestructure of claim 38, wherein a packing density of the microneedles isat least 2 microneedles per square millimeter.
 42. The structure ofclaim 38, wherein the penetrating portion is arranged to pierce humanskin and extend at least 100 microns into the skin.
 43. The structure ofclaim 38, wherein the microneedles have a combined skin-penetration areaof at least about 500 square nanometers.
 44. The structure of claim 38,wherein the point is formed at an intersection of at least four surfacesof the penetrating portion.
 45. The structure of claim 38, wherein theproximal portion is formed integral with the base portion.
 46. Thestructure of claim 38, wherein each penetrating portion has a swordshape with a symmetrical V-type knife edge at a periphery of thepenetrating portion.
 47. The structure of claim 38, wherein at leastsome of the microneedles are coated with a substance.
 48. The structureof claim 48, wherein the substance comprises one or more of lidocaine,bupivacaine, and tetracaine.
 49. The structure of claim 38, wherein thebase portions of the first and second pluralities of microneedles areconnected together.
 50. A method for forming a microneedle structure,comprising: providing a layer of material having opposed substantiallyplanar sides; etching the layer of material to define a plurality ofmicroneedles each having a base portion and a penetrating portion suchthat the base portions of the microneedles are arranged at a peripheryof a first closed loop and each of the microneedles extends toward acenter of the first closed loop, wherein the penetrating portions eachhave an approximately hexagon-shaped cross section, and wherein thepenetrating portions each include a proximal portion and an opposingdistal portion, the proximal portion extending from the base portion andthe distal portion comprising a point.
 51. The method of claim 50,wherein the step of etching is part of a lithographic patterningprocess.
 52. The method of claim 50, wherein the step of etchingincludes isotropic etching of the layer.
 53. The method of claim 50,wherein the point is formed at an intersection of at least foursurfaces.
 54. The method of claim 50, further comprising: etching thelayer of material to define a second plurality of microneedles with baseportions arranged at a periphery of a second closed loop that isarranged around the first closed loop, wherein the second plurality ofmicroneedles each extend away from the center of the first closed loop.55. The method of claim 50, further comprising: bending penetratingportions of the first plurality of microneedles away from the plane ofthe first closed loop.
 56. The method of claim 50, further comprising:exposing both sides of the layer, separately or simultaneously, toetching conditions, such that the steps of etching occurs on both sidesof the layer of material.
 57. A microneedle structure comprising: afirst plurality of microneedles that each includes a base portion and apenetrating portion, the base portions of the first plurality ofmicroneedles being arranged at the periphery of a first closed looplying in a plane, the penetrating portions of the first plurality ofmicroneedles each being bent upwardly from the plane and extending at arespective angle away from the plane of the first closed loop, whereinthe penetrating portions each have an approximately hexagon-shapedlateral cross section, and wherein the penetrating portions each includea proximal portion and an opposing distal portion, the proximal portionextending from the base portion and the distal portion comprising apoint.